Biaryl inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton&#39;s tyrosine kinase and which exhibit desirable characteristics for the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/108,755, filed Aug. 22, 2018, which is a continuation of U.S.application Ser. No. 15/699,857, filed Sep. 8, 2017, now U.S. Pat. No.10,081,619, which is a continuation application of U.S. application Ser.No. 15/103,749, filed Jun. 10, 2016, now issued as U.S. Pat. No.9,809,577, which is a 35 U.S.C. § 371 national stage filing ofInternational Application No. PCT/US2014/069853, filed Dec. 11, 2014,which claims priority to U.S. provisional patent application No.61/914,886, filed Dec. 11, 2013. The entire contents of each of theforegoing applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Protein kinases are a large multigene family consisting of more than 500proteins which play a critical role in the development and treatment ofa number of human diseases in oncology, neurology and immunology. TheTec kinases are non-receptor tyrosine kinases which consists of fivemembers (Tec (tyrosine kinase expressed in hepatocellular carcinoma),Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducibleT-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocytekinase; also known as Txk) and Bmx (bone-marrow tyrosine kinase gene onchromosome X; also known as Etk)) and are primarily expressed inhaematopoietic cells, although expression of Bmx and Tec has beendetected in endothelial and liver cells. Tec kinases (Itk, Rlk and Tec)are expressed in T cell and are all activated downstream of the T-cellreceptor (TCR). Btk is a downstream mediator of B cell receptor (BCR)signaling which is involved in regulating B cell activation,proliferation, and differentiation. More specifically, Btk contains a PHdomain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3).PIP3 binding induces Btk to phosphorylate phospholipase C (PLCγ), whichin turn hydrolyzes PIP2 to produce two secondary messengers, inositoltriphosphate (IP3) and diacylglycerol (DAG), which activate proteinkinase PKC, which then induces additional B-cell signaling. Mutationsthat disable Btk enzymatic activity result in XLA syndrome (X-linkedagammaglobulinemia), a primary immunodeficiency. Given the criticalroles which Tec kinases play in both B-cell and T-cell signaling, Teckinases are targets of interest for autoimmune disorders.

Consequently, there is a great need in the art for effective inhibitorsof Btk. The present invention fulfills these and other needs.

SUMMARY OF THE INVENTION

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, Q¹, Q², Q³, A¹, A², and A³ is as defined and described inclasses and subclasses herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In some embodiments, the present invention provides a compound offormula I:

-   or a pharmaceutically acceptable salt thereof, wherein:-   one of A¹ and A² is C—R⁶, and the other of A¹ and A² is C—R⁶ or N;-   A³ is selected from C—H or N, and is C—H when A¹ or A² is N;-   Q¹ is selected from C—R⁷ and N;-   Q² is selected from C—R⁷ and N;-   Q³ is selected from C—R⁷ and N;    -   wherein at most one of Q¹, Q², and Q³ is N;-   R¹ is —N(R)₂ or an optionally substituted group selected from    phenyl, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic carbocyclyl,    7- to 10-membered saturated or partially unsaturated bicyclic    heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, and 8- to    10-membered bicyclic aryl;-   R² is H or optionally substituted C₁₋₆ aliphatic,    -   or R¹ and R², together with their intervening atoms, form an        optionally substituted ring selected from 3- to 7-membered        saturated or partially unsaturated monocyclic heterocyclyl        having 1-2 heteroatoms selected from oxygen, nitrogen, or        sulfur, 7- to 10-membered bicyclic heterocyclyl having 1-4        heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to        10-membered bicyclic heteroaryl having 1-4 heteroatoms selected        from oxygen, nitrogen;-   R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, and    optionally substituted C₁₋₆ aliphatic;-   R⁴ is selected from halogen, —NO₂, —CN, —OR, —SR, —N(R)₂, —C(O)R,    —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,    —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, and optionally    substituted C₁₋₆ aliphatic;    -   or R³ and R⁴, together with their intervening atoms, form an        optionally substituted fused Ring A, wherein fused Ring A is        selected from fused 5- to 7-membered monocyclic carbocycle and        fused 5- to 7-membered heterocycle having 1-2 heteroatoms        selected from oxygen, nitrogen, or sulfur;-   R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic carbocyclyl,    7- to 10-membered saturated or partially unsaturated bicyclic    heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to    10-membered bicyclic aryl;-   each of R⁶ and R⁷ is independently selected from H, halogen, —NO₂,    —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂,    or optionally substituted C₁₋₆ aliphatic; and-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, 3- to 8-membered saturated or    partially unsaturated carbocyclyl ring, 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, or:-   two R groups on the same nitrogen are taken together with their    intervening atoms to form an optionally substituted ring selected    from 3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur.

Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In some embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refersto a monocyclic C₃-C₇ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “fused 5- to 7-membered monocyclic carbocycle” refers to amonocyclic hydrocarbon that shares three carbon atoms with the corestructure. By way of illustration, the compound of Example I-90possesses a 5-membered fused monocyclic carbocycle, as indicated by thedotted lines below:

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic andbicyclic ring systems having a total of five to 10 ring members, whereinat least one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In some embodiments, an 8-10membered bicyclic aryl group is an optionally substituted naphthyl ring.In certain embodiments of the present invention, “aryl” refers to anaromatic ring system which includes, but not limited to, phenyl,biphenyl, naphthyl, anthracyl and the like, which may bear one or moresubstituents. Also included within the scope of the term “aryl,” as itis used herein, is a group in which an aromatic ring is fused to one ormore non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. Heteroarylgroups include, without limitation, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroarl”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5- to7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety thatis either saturated or partially unsaturated, and having, in addition tocarbon atoms, one or more, preferably one to four, heteroatoms, asdefined above. When used in this context in reference to a ring atom,the term “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,”“heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

The term “fused 5- to 7-membered monocyclic heterocycle” refers to amonocyclic heterocyclic moiety that shares three carbon atoms with thecore structure. By way of illustration, the compound of Example I-98possesses a 6-membered fused monocyclic heterocycle, as indicated by thedotted lines below:

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may, when specified,contain “optionally substituted” moieties. In general, the term“substituted,” whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. Combinations of substituents envisioned bythis invention are preferably those that result in the formation ofstable or chemically feasible compounds. The term “stable,” as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄ SR^(∘); —(CH₂)₀₋₄ Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘)C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘)C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄ SR—, SC(S)SR^(∘); —(CH₂)₀₋₄ SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄ SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄ S(O)₂₀R^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄ S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘)S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; OP(O)R^(∘))₂; —OP(O)(OR^(∘)) ₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘)) ₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference.

In certain embodiments, the neutral forms of the compounds areregenerated by contacting the salt with a base or acid and isolating theparent compound in the conventional manner. In some embodiments, theparent form of the compound differs from the various salt forms incertain physical properties, such as solubility in polar solvents.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom, thereby forming a carbonyl.

One of ordinary skill in the art will appreciate that the syntheticmethods, as described herein, utilize a variety of protecting groups. Bythe term “protecting group,” as used herein, it is meant that aparticular functional moiety, e.g., O, S, or N, is masked or blocked,permitting, if desired, a reaction to be carried out selectively atanother reactive site in a multifunctional compound. Suitable protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, the entirety of which isincorporated herein by reference. In certain embodiments, a protectinggroup reacts selectively in good yield to give a protected substratethat is stable to the projected reactions; the protecting group ispreferably selectively removable by readily available, preferablynon-toxic reagents that do not attack the other functional groups; theprotecting group forms a separable derivative (more preferably withoutthe generation of new stereogenic centers); and the protecting groupwill preferably have a minimum of additional functionality to avoidfurther sites of reaction. As detailed herein, oxygen, sulfur, nitrogen,and carbon protecting groups may be utilized. Amino-protecting groupsinclude methyl carbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2,7-dibromo)fluoroenylmethyl carbamate, 4-methoxyphenacyl carbamate(Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc),2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC),allyl carbamate (Alloc), 4-nitrocinnamyl carbamate (Noc),N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate(Cbz), p-nitobenzyl carbamate, p-chlorobenzyl carbamate, diphenylmethylcarbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethylcarbamate, 2,4-dimethylthiophenyl carbamate (Bmpc),2-triphenylphosphonioisopropyl carbamate (Ppoc),m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate,m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methyl carbamate,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, t-amyl carbamate, p-cyanobenzyl carbamate, cyclohexylcarbamate, cyclopentyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, 2-furanylmethyl carbamate,isoborynl carbamate, isobutyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide,o-nitrophenoxyacetamide, acetoacetamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-2,5-dimethylpyrrole,N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine(SEM), N-3-acetoxypropylamine, N-benzylamine, N-triphenylmethylamine(Tr), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative, N-nitroamine,N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp),dimethylthiophosphinamide (Mpt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamideExemplary protecting groups are detailed herein, however, it will beappreciated that the present invention is not intended to be limited tothese protecting groups; rather, a variety of additional equivalentprotecting groups can be readily identified using the above criteria andutilized in the method of the present invention. Additionally, a varietyof protecting groups are described by Greene and Wuts (supra).

The symbol “

”, except when used as a bond to depict unknown or mixedstereochemistry, denotes the point of attachment of a chemical moiety tothe remainder of a molecule or chemical formula.

Compounds

As described above, in certain embodiments provided compounds are offormula I:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, Q¹, Q², Q³, A¹, A², and A³ is as defined above and describedin classes and subclasses herein, both singly and in combination.

As used herein, unless otherwise stated, references to formula I alsoinclude all subgenera of formula I defined and described herein (e.g.,formulae I′, I-a, II-a, II-b, II-c, III, IV-a, IV-b, IV-c, V-a, V-b,VI-a, VI-b, VII-a, VII-b, VII-c and VII-d).

In some embodiments, A¹ and A² are C—R⁶ and A³ is C—H. In someembodiments, A¹ is C—R⁶, A² is N, and A³ is C—H. In some embodiments, A¹is C—R⁶, A² is C—R⁶, and A³ is N. In some embodiments, A¹ is N, A² isC—R⁶, and A³ is C—H.

In some embodiments, Q¹, Q², and Q³ are C—R⁷. In some embodiments, Q¹ isN, and Q² and Q³ are C—R⁷. In some embodiments, Q² is N, and Q¹ and Q³are C—R⁷. In some embodiments, Q³ is N, and Q¹ and Q² are C—R⁷.

In certain embodiments, R¹ is an optionally substituted group selectedfrom 5- to 6-membered heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, phenyl, or 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur.

In some embodiments, R¹ is optionally substituted phenyl. In someembodiments, R¹ is phenyl substituted with halogen.

In some embodiments, R¹ is optionally substituted 5-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. Insome embodiments, R¹ is an optionally substituted group selected fromthiazolyl, pyrazolyl, isoxazolyl, or thiophenyl. In some embodiments, R¹is thiazolyl, pyrazolyl, or isoxazolyl substituted with t-butyl or —CF₃.

In some embodiments, R¹ is optionally substituted 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. Insome embodiments, R¹ is optionally substituted pyridyl. In someembodiments, R¹ is pyridyl substituted with t-butyl or —CF₃.

In other embodiments, R¹ is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur. In someembodiments, R¹ is an optionally substituted group selected frompiperidinyl or azetidinyl. In some embodiments, R¹ is piperidinylsubstituted with t-butyl or —CF₃. In some embodiments, R¹ is azetidinylsubstituted with —OC₁₋₆ alkyl.

In some embodiments, R¹ is optionally substituted 7- to 10-memberedsaturated or partially unsaturated bicyclic heterocyclyl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur. In someembodiments, R¹ is optionally substituted 7- to 10-membered bicyclicheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur.

In some embodiments, R¹ is optionally substituted with one or moregroups selected from halogen, C₁₋₆ aliphatic optionally substituted withhalogen, or —OR.

In some embodiments, R¹ is selected from:

In certain embodiments, R¹ is

In certain embodiments, R¹ is

In certain embodiments, R¹ is

In certain embodiments, R¹ is

In some embodiments, R¹ is —N(R)₂. In some embodiments, R¹ is —N(R)₂ andR is an optionally substituted group selected from phenyl, 3- to8-membered saturated or partially unsaturated carbocyclyl ring, 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur. In some embodiments, R¹ is —N(R)₂ and R is a 3- to8-membered saturated or partially unsaturated carbocyclyl ring.

In some embodiments, R² is hydrogen. In some embodiments, R² isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R² ismethyl.

In some embodiments, R¹ and R², together with their intervening atoms,form an optionally substituted ring selected from 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedbicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, or 7- to 10-membered bicyclic heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen.

In some embodiments, when R¹ and R² are taken together they form a 7- to10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, optionally substituted with C₁₋₆ aliphatic.In some embodiments, when R¹ and R² are taken together they form a 7- to10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, optionally substituted with t-butyl orcyclopropyl. In some embodiments, R¹ and R² are taken together to form a7- to 10-membered bicyclic heterocyclyl selected from:

In some embodiments, R³ is hydrogen. In some embodiments, R³ isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R³ is C₁₋₆alkyl. In some embodiments, R³ is methyl.

In certain embodiments, R⁴ is halogen, —OR, —SR, —N(R)₂, —C(O)R,—C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R,—N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or optionally substituted C₁₋₆aliphatic. In some embodiments, R⁴ is optionally substituted C₁₋₆aliphatic. In some embodiments, R⁴ is C₁₋₆ alkyl. In some embodiments,R⁴ is methyl. In some embodiments, R⁴ is trifluoromethyl.

In some embodiments, R⁴ is halogen.

In certain embodiments, R³ and R⁴, together with their interveningatoms, form optionally substituted fused Ring A (indicated by the dottedlines in the structure below):

Fused Ring A is selected from fused 5- to 7-membered monocycliccarbocycle and 5- to 7-membered monocyclic heterocycle having 1-2heteroatoms selected from oxygen, nitrogen, and sulfur.

In some embodiments, fused Ring A is fused 5- to 7-membered monocycliccarbocycle. In some embodiments, fused Ring A is fused 7-memberedmonocyclic carbocycle. It is to be understood that in the context of“fused Ring A,” the carbon chain formed by R³ and R⁴ is a saturatedcarbon chain. For example, in the compound of Example 90, fused Ring A(indicated by dotted lines in the structure below) is a five-memberedring in which R³ and R⁴ form a —CH₂—CH₂— chain:

In some embodiments, fused Ring A is fused 5- to 7-membered monocyclicheterocycle having 1 heteroatom selected from oxygen or nitrogen. It isto be understood that in the context of “fused Ring A,” the chain formedby R³ and R⁴ is a saturated chain. For example, in the compound ofExample 98, fused Ring A (indicated by dotted lines in the structurebelow) is a six-membered ring in which R³ and R⁴ form a —CH₂—O—CH₂—chain:

In some embodiments, fused Ring A is fused 5-membered monocyclicheterocycle having 1 oxygen. In some embodiments, fused Ring A is fused6-membered monocyclic heterocycle having 1 oxygen. In some embodiments,fused Ring A is fused 7-membered monocyclic heterocycle having 1 oxygen.In some embodiments, fused Ring A is fused 5-membered monocyclicheterocycle having 1 nitrogen. In some embodiments, fused Ring A isfused 6-membered monocyclic heterocycle having 1 nitrogen. In someembodiments, fused Ring A is fused 7-membered monocyclic heterocyclehaving 1 nitrogen.

In some embodiments, R⁵ is selected from hydrogen, —C(O)R, or optionallysubstituted 5- to 6-membered heteroaryl having 1-4 heteroatoms selectedfrom oxygen, nitrogen, or sulfur. In some embodiments, R⁵ is hydrogen.In some embodiments, R⁵ is —C(O)R, wherein R is C₁₋₆ aliphatic. In someembodiments, R⁵ is —C(O)Me.

In some embodiments, R⁵ is optionally substituted 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur. In some embodiments, R⁵ is an optionally substituted groupselected from pyrazolyl, imidazolyl, isoxazolyl, triazolyl, tetrazolyl,thiadiazolyl, or pyridyl.

In some embodiments, R⁵ is pyrazolyl optionally substituted with methyl,ethyl, isopropyl, —(CH₂)₂OH, —(CH₂)₂OMe, —(CH₂)₂NH₂, —CH₂CHOHCH₂NH₂,—CH₂CHNH₂COOH, —CH₂CHNH₂CH₂OH, —CH₂-morpholinyl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, cyclobutyl, piperidinyl, or cyclohexyl, any ofwhich may be substituted with C₁₋₆ aliphatic, hydroxyl, or carboxyl.

In some embodiments, R⁵ is pyridyl optionally substituted withpiperazinyl.

In some embodiments, R⁵ is imidazolyl optionally substituted with C₁₋₆aliphatic.

In some embodiments, R⁵ is triazolyl optionally substituted with C₁₋₆aliphatic.

In some embodiments, R⁵ is an optionally substituted group selectedfrom:

In some embodiments, said groups are substituted with one or moremoieties selected from methyl, ethyl, isopropyl, —C(O)OC₁₋₆ alkyl;—(CH₂)₂OH, —(CH₂)₂OMe, —(CH₂)₂NH₂, —CH₂CHOHCH₂NH₂, —CH₂CHNH₂COOH,—C(CH₃)₂C(O)NH₂, —CH₂CHNH₂CH₂OH, —CH₂-morpholinyl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, cyclobutyl, piperidinyl, piperizinyl, orcyclohexyl, any of which may be substituted with C₁₋₆ aliphatic,halogen, hydroxyl, or carboxyl.

In some embodiments, R⁵ is

In some embodiments, each R⁶ is independently selected from hydrogen,halogen, or C₁₋₆ aliphatic. In some embodiments, each R⁶ isindependently selected from hydrogen, fluoro, or methyl. In someembodiments, each R⁶ is hydrogen.

In certain embodiments, each R⁷ is independently selected from hydrogenor halogen. In some embodiments, each R⁷ is hydrogen. In someembodiments, when R⁴ is halogen, one R⁷ is halogen and other R⁷ groupsare hydrogen.

In some embodiments, provided compounds are of formula I′:

-   or a pharmaceutically acceptable salt thereof, wherein:-   one of A¹ and A² is C—R⁶, and the other of A¹ and A² is selected    from C—R⁶ or N;-   A³ is selected from C—H or N, and is C—H when A¹ or A² is N;-   Q¹ is selected from C—R⁷ and N;-   Q² is selected from C—R⁷ and N;-   Q³ is selected from C—R⁷ and N;    -   wherein at most one of Q¹, Q², and Q³ is N;-   R¹ is selected from —N(R)₂, phenyl, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 7- to 10-membered saturated or partially    unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, 7- to 10-membered    bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, wherein    said phenyl, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic carbocyclyl,    7- to 10-membered saturated or partially unsaturated bicyclic    heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to    10-membered bicyclic aryl are optionally substituted with one or    more R¹⁰;-   R² is H or C₁₋₆ aliphatic;    -   or R¹ and R², together with their intervening atoms, form a ring        selected from 3- to 7-membered saturated or partially        unsaturated monocyclic heterocyclyl having 1-2 heteroatoms        selected from oxygen, nitrogen, or sulfur, 7- to 10-membered        bicyclic heterocyclyl having 1-4 heteroatoms selected from        oxygen, nitrogen, or sulfur, or 7- to 10-membered bicyclic        heteroaryl having 1-4 heteroatoms selected from oxygen,        nitrogen, wherein said ring is optionally substituted with one        or more R²⁰;-   R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, and    C₁₋₆ aliphatic, wherein the C₁₋₆ aliphatic group is optionally    substituted with hydroxyl;-   each R⁴ is independently selected from halogen, —NO₂, —CN, —OR, —SR,    —N(R)₂, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,    —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆    aliphatic, wherein said C₁₋₆ aliphatic is optionally substituted    with one or more R⁴⁰;    -   or R³ and R⁴ together with their intervening atoms form fused        Ring A selected from fused 5- to 7-membered monocyclic        carbocycle, fused 5- to 7-membered monocyclic heterocycle having        1-2 heteroatoms selected from oxygen, nitrogen, or sulfur,        wherein said fused Ring A is optionally substituted with one or        more R⁴⁰;-   R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    or C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic carbocyclyl, 7- to 10-membered saturated or partially    unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, or 8- to 10-membered bicyclic aryl, wherein said C₁₋₆    aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic carbocyclyl, 7- to 10-membered saturated or partially    unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, or 8- to 10-membered bicyclic aryl, are optionally    substituted with one or more R⁵⁰;-   each of R⁶ and R⁷ is independently selected from H, halogen, —NO₂,    —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂,    or C₁₋₆ aliphatic;-   each R is independently hydrogen or C₁₋₆ aliphatic, phenyl, 3- to    8-membered saturated or partially unsaturated carbocyclyl ring, 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein said C₁₋₆    aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated carbocyclyl ring, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, are optionally substituted with one or more R⁵⁰; or    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a ring selected from 3- to 7-membered        saturated or partially unsaturated monocyclic heterocyclyl        having 1-2 heteroatoms selected from oxygen, nitrogen, or        sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms        selected from oxygen, nitrogen, or sulfur, wherein said ring is        optionally substituted with one or more R⁵⁰;-   each R¹⁰ is independently selected from halogen, —OR^(10a),    C₁₋₆aliphatic, 3- to 5-membered saturated or partially unsaturated    carbocyclyl, 3- to 5-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, 3- to 5-membered    saturated or partially unsaturated carbocyclyl, 3- to 5-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, are    optionally substituted with one or more R¹⁵;-   each R¹⁵ is independently selected from halogen and —OR^(15a);-   R^(10a) is C₁₋₆alkyl optionally substituted with halogen;-   R^(15a) is C₁₋₆alkyl;-   each R²⁰ is independently selected from halogen, C₁₋₆ aliphatic, 3-    to 5-membered saturated or partially unsaturated carbocyclyl, 3- to    5-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur, wherein said C₁₋₆ aliphatic, 3- to 5-membered saturated    or partially unsaturated carbocyclyl, 3- to 5-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, are optionally    substituted with one or more R¹⁵;-   each R⁴⁰ is independently selected from halogen, C₁₋₆ alkyl, 4- to    6-membered monocyclic heterocyclyl having 1-2 heteroatoms selected    from carbon, nitrogen, or sulfur, —C(O)H, —N(R^(40a))₂,    —N(R^(40a))C(O)(R^(40b)), —N(R^(40a))C(O)₂(R^(40a)), —OR^(40a),    —SR^(40a), and —C(O)₂R^(40a), wherein said C₁₋₆ alkyl group is    optionally substituted with halogen or —OR^(40a);-   each R^(40a) is independently selected from H and C₁₋₆alkyl; or two    R^(40a) groups on the same nitrogen are taken together with their    intervening atoms to form a ring selected from 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   each R^(40b) is independently selected from C₂₋₆ alkenyl and 5- or    6-membered heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur, wherein said 5- or 6-membered heterocyclyl    having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, is    optionally substituted with one or more R⁴⁵;-   R⁴⁵ is C₁₋₆ alkyl;-   each R⁵⁰ is independently selected from    -   C₁₋₆ aliphatic, —OR^(50a), —N(R^(50a))₂, —C(O)N(R^(50a))₂,        —C(O)₂R^(50a), oxo, 3- to 6-membered saturated or partially        unsaturated monocyclic carbocyclyl, 3- to 6-membered saturated        or partially unsaturated monocyclic heterocyclyl having 1-2        heteroatoms selected from oxygen, nitrogen, or sulfur, and 3- to        10-membered heterocyclyalkyl having 1-4 heteroatoms selected        from oxygen, nitrogen, or sulfur, wherein said C₁₋₆ alkyl, 3- to        6-membered saturated or partially unsaturated monocyclic        carbocyclyl, 3- to 6-membered saturated or partially unsaturated        monocyclic heterocyclyl having 1-2 heteroatoms selected from        oxygen, nitrogen, or sulfur, and 3- to 10-membered        heterocyclyalkyl having 1-4 heteroatoms selected from oxygen,        nitrogen, or sulfur, are optionally substituted with one or more        R⁵⁵;-   R^(50a) is selected from H and C₁₋₆ alkyl;-   each R⁵⁵ is independently selected from 5- to 6-membered    heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen,    or sulfur, C₁₋₆ alkyl, —OR^(55a), —C(O)N(R^(55a))₂, halogen,    —N(R^(55a))₂, —C(O)₂R^(55a), —S(O)₂R^(55b), and —S(O)₂(NR^(55a))₂;-   R^(55a) is selected from H and C₁₋₆alkyl, wherein said C₁₋₆ alkyl is    optionally substituted with halogen; and-   R^(55b) is C₁₋₆ alkyl.

In some embodiments, provided compounds are of formula I′ or apharmaceutically acceptable salt thereof, wherein:

-   one of A¹ and A² is C—R⁶, and the other of A¹ and A² is selected    from C—R⁶ or N;-   A³ is selected from C—H or N, and is C—H when A¹ or A² is N;-   Q¹ is selected from C—R⁷ and N;-   Q² is selected from C—R⁷ and N;-   Q³ is selected from C—R⁷ and N;    -   wherein at most one of Q¹, Q², and Q³ is N;-   R¹ is selected from —N(R)₂, phenyl, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 7- to 10-membered saturated or partially    unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, 7- to 10-membered    bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, wherein    said phenyl, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic carbocyclyl,    7- to 10-membered saturated or partially unsaturated bicyclic    heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to    10-membered bicyclic aryl are optionally substituted with one or    more R¹⁰;-   R² is H or C₁₋₆ aliphatic;    -   or R¹ and R², together with their intervening atoms, form a ring        selected from 3- to 7-membered saturated or partially        unsaturated monocyclic heterocyclyl having 1-2 heteroatoms        selected from oxygen, nitrogen, or sulfur, 7- to 10-membered        bicyclic heterocyclyl having 1-4 heteroatoms selected from        oxygen, nitrogen, or sulfur, or 7- to 10-membered bicyclic        heteroaryl having 1-4 heteroatoms selected from oxygen,        nitrogen, wherein said ring is optionally substituted with one        or more R²⁰;-   R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, and    C₁₋₆ aliphatic, wherein the C₁₋₆ aliphatic group is optionally    substituted with hydroxyl;-   each R⁴ is independently selected from halogen, —NO₂, —CN, —OR, —SR,    —N(R)₂, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,    —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆    aliphatic, wherein said C₁₋₆ aliphatic is optionally substituted    with one or more R⁴⁰;    -   or R³ and R⁴ together with their intervening atoms form fused        Ring A selected from fused 5- to 7-membered monocyclic        carbocycle, fused 5- to 7-membered monocyclic heterocycle having        1-2 heteroatoms selected from oxygen, nitrogen, or sulfur,        wherein said fused Ring A is optionally substituted with one or        more R⁴⁰;-   R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    or C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic carbocyclyl, 7- to 10-membered saturated or partially    unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, or 8- to 10-membered bicyclic aryl, wherein said C₁₋₆    aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic carbocyclyl, 7- to 10-membered saturated or partially    unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, or 8- to 10-membered bicyclic aryl, are optionally    substituted with one or more R⁵⁰;-   each of R⁶ and R⁷ is independently selected from H, halogen, —NO₂,    —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂,    —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂,    or C₁₋₆ aliphatic;-   each R is independently hydrogen or C₁₋₆ aliphatic, phenyl, 3- to    8-membered saturated or partially unsaturated carbocyclyl ring, 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein said C₁₋₆    aliphatic, phenyl, 3- to 7-membered saturated or partially    unsaturated carbocyclyl ring, 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, are optionally substituted with one or more R⁵⁰; or    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a ring selected from 3- to 7-membered        saturated or partially unsaturated monocyclic heterocyclyl        having 1-2 heteroatoms selected from oxygen, nitrogen, or        sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms        selected from oxygen, nitrogen, or sulfur, wherein said ring is        optionally substituted with one or more R⁵⁰;-   each R¹⁰ is independently selected from halogen, —OR^(10a),    C₁₋₆aliphatic, 3- to 5-membered saturated or partially unsaturated    carbocyclyl, 3- to 5-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, 3- to 5-membered    saturated or partially unsaturated carbocyclyl, 3- to 5-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, are    optionally substituted with one or more R¹⁵;-   each R¹⁵ is independently selected from halogen and —OR^(15a);-   R^(10a) is C₁₋₆alkyl;-   R^(15a) is C₁₋₆alkyl;-   each R²⁰ is independently selected from halogen, C₁₋₆ aliphatic, 3-    to 5-membered saturated or partially unsaturated carbocyclyl, 3- to    5-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur,-   wherein said C₁₋₆ aliphatic, 3- to 5-membered saturated or partially    unsaturated carbocyclyl, 3- to 5-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, are optionally substituted with    one or more R¹⁵;-   each R⁴⁰ is independently selected from halogen, 4- to 6-membered    monocyclic heterocyclyl, —N(R^(40a))₂, —N(R^(40a))C(O)(R^(40b)),    —N(R^(40a))C(O)₂(R^(40a)), —OR^(40a), SR^(40a)a, and C(O)₂R^(40a);-   each R^(40a) is independently selected from H and C₁₋₆alkyl; or two    R^(40a) groups on the same nitrogen are taken together with their    intervening atoms to form a ring selected from 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   each R^(40b) is independently selected from C₂₋₆ alkenyl and 5- or    6-membered heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur, wherein said 5- or 6-membered heterocyclyl    having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, is    optionally substituted with one or more R⁴⁵;-   R⁴⁵ is C₁₋₆ alkyl;-   each R⁵⁰ is independently selected from C₁₋₆ alkyl, —OR^(50a),    —N(R^(50a))₂, —C(O)N(R^(50a))₂; —C(O)₂R^(50a); 3- to 6-membered    saturated or partially unsaturated monocyclic carbocyclyl, 3- to    6-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur, and 3- to 10-membered heterocyclyalkyl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, wherein said    C₁₋₆ alkyl, 3- to 6-membered saturated or partially unsaturated    monocyclic carbocyclyl, 3- to 6-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, and 3- to 10-membered    heterocyclyalkyl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, are optionally substituted with one or more    R⁵⁵;-   R^(50a) is selected from H and C₁₋₆alkyl;-   each R⁵⁵ is independently selected from 5- to 6-membered    heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen,    or sulfur, C₁₋₆ alkyl, —OR^(55a), —N(R^(55a))₂, —C(O)₂R^(55a),    —S(O)₂R^(55b), and —S(O)₂(NR^(55a))₂;-   R^(55a) is selected from H and C₁₋₆alkyl; and-   R^(55b) is C₁₋₆ alkyl.

In some embodiments, provided compounds are of formula II-a, II-b, orII-c:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, Q¹, Q², and Q³ is as defined above and described in classesand subclasses herein, both singly and in combination.

In some embodiments, Q¹, Q², and Q³ are each C—R⁷ and R⁷ is hydrogen. Insome embodiments, provided compounds are of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, A¹, A², and A³ is as defined above and described in classesand subclasses herein, both singly and in combination.

In certain embodiments, one of Q¹, Q², and Q³ is N, the other two areC—R⁷, and R⁷ is hydrogen. In some embodiments, provided compounds are offormula IV-a, IV-b, or IV-c:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, A¹, A², and A³ is as defined above and described in classesand subclasses herein, both singly and in combination.

In some embodiments, provided compounds are of formula V-a or V-b:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, and R⁵ is as defined above and described in classes andsubclasses herein, both singly and in combination.

In certain embodiments, provided compounds are of formula VI-a, VI-b,VI-c, or VI-d:

or a pharmaceutically acceptable salt thereof, wherein each of fusedRing A, R¹, R², R³, and R⁵ is as defined above and described in classesand subclasses herein, both singly and in combination.

In certain embodiments, provided compounds are of formula VII-a, VII-b,VII-c, or VII-d:

or a pharmaceutically acceptable salt thereof, wherein:R⁴ is methyl or CF₃; and the

moiety is optionally substituted with one or more groups selected fromC₁₋₆ aliphatic, pyrrolidinyl, piperidinyl, or cyclohexyl, any of whichmay be optionally substituted with hydroxyl, C₁₋₆ aliphatic, orcarboxyl.

In certain embodiments, provided compounds are of formula VIII-a,VIII-b, or VIII-c:

or a pharmaceutically acceptable salt thereof, wherein: R^(10a) is C₁₋₆alkyl, R⁴ is methyl or CF₃, and the

moieties are optionally substituted with one or more C₁₋₆ aliphaticgroups.

In certain embodiments, provided compounds are of formula IX:

or a pharmaceutically acceptable salt thereof, wherein:R^(10a) is C₁₋₆ alkyl and the

moiety is optionally substituted with one or more C₁₋₆ aliphatic groups.

In some embodiments, a provided compound is a compound selected from thefollowing, or a pharmaceutically acceptable salt thereof:2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-1),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-2),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-3),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-4),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-5),5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)picolinamide(I-6),4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(I-7),3,4-dichloro-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(I-8),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide(I-9),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-2-carboxamide(I-10),trans-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamide(I-11),2-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one(I-12),2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(I-13),4-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-14),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxamide(I-15),1-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-4-carboxamide(I-16),cis-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamide(I-17),5-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-4-carboxamide(I-18),N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)piperidine-1-carboxamide(I-19),4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-1-carboxamide(I-20),3-isopropoxy-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-21),1-(bicyclo[2.2.2]octan-1-yl)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)urea(I-22),4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazine-1-carboxamide(I-23),2-isopropyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)morpholine-4-carboxamide(I-24),2-(tert-butyl)-N-(2-methyl-4-(2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-25),2-(tert-butyl)-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-26),(R)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-27),(S)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-28),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyridin-4-yl)ethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-29),2-(tert-butyl)-N-(4-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-30),2-(tert-butyl)-N-(4-(2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-31),2-(tert-butyl)-N-(2-methyl-4-(2-((pyridin-4-ylmethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-32),2-(tert-butyl)-N-(2-methyl-4-(2-(methylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-33),2-(tert-butyl)-N-(4-(2-(ethylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-34),2-(tert-butyl)-N-(4-(2-(isopropylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-35),N-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-36),2-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-37),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-38),2-(tert-butyl)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-39),2-(tert-butyl)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-40),2-(tert-butyl)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-41),N-(4-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-42),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-43),3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarboxylicacid (I-44),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(1-45),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-46),2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-47),cis-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (I-48),trans-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (I-49),N-(4-(2-((1-(2-aminoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-50),2-(tert-butyl)-N-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-51),2-(tert-butyl)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-52),2-(tert-butyl)-N-(2-methyl-4-(2-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-53),2-(tert-butyl)-N-(2-methyl-4-(2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-54),2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-55),2-(tert-butyl)-N-(4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-56),2-(tert-butyl)-N-(2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-57),2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-58),2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-59),2-(tert-butyl)-N-(2-methyl-4-(2-(pyridin-2-ylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-60),2-(tert-butyl)-N-(4-(2-((5-(dimethylamino)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-61),2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-62),2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-63),2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-64),2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-65),2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-66),2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-67),2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-tetrazol-5-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-68),2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-69),2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzyl)thiazole-5-carboxamide(I-70),2-(tert-butyl)-N-(2-methyl-4-(2-(1-methylpiperidine-4-carboxamido)pyridin-4-yl)benzyl)thiazole-5-carboxamide(I-71),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide(I-72),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxamide(I-73),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide(I-74),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(I-75), N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide (I-76),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(I-77),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(I-78),(7R,9aR)—N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide(I-79),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide(I-80),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide(I-81),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(I-82),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-83),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-84),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-cyclopropylthiazole-5-carboxamide(I-85),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-isopropylthiazole-5-carboxamide(1-86),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(1-methoxyethyl)thiazole-5-carboxamide(I-87),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tetrahydrofuran-2-yl)thiazole-5-carboxamide(I-88),2-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)thiazole-5-carboxamide(I-89),2-(tert-butyl)-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)thiazole-5-carboxamide(I-90),2-(tert-butyl)-N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-91),2-(tert-butyl)-N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-92),N-(6-(6-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamide(I-93),N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-94),N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-95),2-(tert-butyl)-N-(6-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-96),2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)thiazole-5-carboxamide(I-97),2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)thiazole-5-carboxamide(I-98),2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamide(I-99),2-(tert-butyl)-N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)thiazole-5-carboxamide(I-100),N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-101),2-(tert-butyl)-N-((6-methyl-2′-((1-methyl-1H-pyrazol-4-yl)amino)-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide(I-102),2-(tert-butyl)-N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)thiazole-5-carboxamide(I-103),N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-104),N-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-105),2-(tert-butyl)-N-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide(I-106),N-(1-(4-(2-aminopyrimidin-4-yl)-2-methylphenyl)ethyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-107),2-(tert-butyl)-N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide(I-108),N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-109),N-(4-(2-amino-5-fluoropyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-110),2-(tert-butyl)-N-(4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-111),2-(tert-butyl)-N-(2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-112),N-((5-(2-aminopyrimidin-4-yl)-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-113),2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyridazin-4-yl)benzyl)thiazole-5-carboxamide(I-114),N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-115),2-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)thiazole-5-carboxamide.(I-116),N-(2-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-117),2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-118),N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-119),N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-120),3-isopropoxy-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-121),(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-122),(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-123),(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-124),(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-125),(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-126),(R)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-127),(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-128),(S)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-129),(S)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid (I-130),(S)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-131),(R)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid (I-132),(R)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-133),2-(tert-butyl)-N-(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-134),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-135),N-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamide(I-136),N-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-137),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxamide5,5-dioxide (I-138),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-139),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-140),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-141),N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-142),N-(4-(6-acetamidopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-143), tert-butyl5-(2-aminopyrimidin-4-yl)-2-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)benzyl(methyl)carbamate(I-144),N-(4-(2-aminopyrimidin-4-yl)-2-((methylamino)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-145),N-(4-(2-aminopyrimidin-4-yl)-2-((N-methylacrylamido)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-146),2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-147),2-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-148), tert-butyl2-((6-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-4-yl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate(I-149),1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-150),2-(tert-butyl)-N-(4-(6-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-151),3-(tert-butoxy)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-152),5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide(I-153),1-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-154),1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-3-carboxamide(I-155),N-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide(I-156),1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-157),1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-2-carboxamide(I-158),N-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide(I-159),3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-160),(R)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-161),(S)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-162),3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-163),(R)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-164),(S)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-165),N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(I-166),3-isopropoxy-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-167),N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(I-168),(R)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(I-169),(S)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(I-170),3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-171),3-isopropoxy-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-172),3-(tert-butoxy)-N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-173),3-(tert-butoxy)-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-174),3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-175),(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-176),(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-177),3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-178),3-(tert-butoxy)-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-179),3-(tert-butoxy)-N-(2-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-180),N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide(I-181),3-(tert-butoxy)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-182),3-Isopropyl-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(I-183),3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(I-184),3-(tert-butyl)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(I-185),3-(tert-butyl)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(I-186),3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide(I-187),3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide(I-188),3-(tert-butoxy)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)azetidine-1-carboxamide(I-189),3-(tert-butoxy)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-190),1-(tert-butyl)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-191),1-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one(I-192),1-(tert-butyl)-N-(4-(6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-193),3-(tert-butyl)-N-(4-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)pyrrolidine-1-carboxamide(I-194),cis-4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (I-195),5-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide(I-196),1-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-197),3-(tert-butoxy)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-198),3-(tert-butoxy)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-199),3-(tert-butoxy)-N-(4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-200),1-(tert-butyl)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide(I-201),1-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide(I-202),3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-203),3-(tert-butoxy)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-204),3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-205),3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide(I-206),3-(tert-butyl)-N-(4-(2-((1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(I-207),3-(tert-butyl)-N-(4-(2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(I-208),3-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(I-209),3-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(I-210),1-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-211),3-isopropoxy-N-(2-methyl-4-(2-((1-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-212),3-isopropoxy-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide(I-213),3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide(I-214),3-(tert-butoxy)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-215),3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide(I-216),N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(I-217),3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-218),3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-219),trans-N-(4-(2-((1-((3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(I-220),3-isopropoxy-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-221),N-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(I-222),3-(tert-butoxy)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide(I-223),3-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(I-224),1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-225),1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-3-carboxamide(I-226),(R)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-227),(S)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-228),(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-229),(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(I-230),1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-231),1-(tert-butyl)-N-(4-(6-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-232),1-(tert-butyl)-N-(4-(6-((5-(2-hydroxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-233),1-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-234),1-(tert-butyl)-N-(4-(6-((5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-235),1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-236),1-(tert-butyl)-N-(4-(6-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-237),3-Ethyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-238),3-(tert-butoxy)-N-(2-methyl-4-(6-((5-methyl-6-oxo-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-239),1-(tert-butyl)-N-(2-chloro-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-240),1-(tert-butyl)-N-(4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide(I-241),1-(tert-butyl)-N-(4-(6-((5,5-dioxido-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-242),3-isopropoxy-N-(2-methyl-4-(6-((1-d3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-243),(S)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(I-244),(R)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(1-245),3-(1,1,1,3,3,3-d6)isopropoxy-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-246),1-(tert-butyl)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(I-247),3-(tert-butoxy)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)azetidine-1-carboxamide(I-248),4-isobutyl-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-2-one(I-249),1-tert-butyl-N-[[4-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrazole-4-carboxamide(1-250),3-tert-butoxy-N-[[2-methyl-4-[6-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-251),1-tert-butyl-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrazole-3-carboxamide(I-252),(3R)-3-tert-butyl-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-253),(3S)-3-tert-butyl-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-254),(3S)-3-isopropyl-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-255),3-tert-butoxy-N-[[2-methyl-4-[6-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-256),1-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrazole-4-carboxamide(I-257),1-tert-butyl-N-[[4-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrazole-4-carboxamide(I-258),3-isopropoxy-N-[[4-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]azetidine-1-carboxamide(I-259),1-tert-butyl-N-[[4-[2-[(1-cyclopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrazole-4-carboxamide(I-260),N-[[4-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]-3-(1,1,1,3,3,3-d6)isopropoxy-azetidine-1-carboxamide(1-262),N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]-3-propyl-azetidine-1-carboxamide(I-263),5-tert-butyl-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide(I-264),5-tert-butyl-N-[[2-methyl-4-[6-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]isoxazole-3-carboxamide(I-265),2-tert-butyl-N-[[2-methyl-4-[6-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-266),2-tert-butyl-N-[[2-methyl-4-[6-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylamino)pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-267),2-tert-butyl-N-[[4-[6-[[7-(2-hydroxyethyl)-6,8-dihydro-5H-2,7-naphthyridin-3-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-268),2-tert-butyl-N-[[2-methyl-4-[6-[(7-methyl-6,8-dihydro-5H-2,7-naphthyridin-3-yl)amino]pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-269),2-tert-butyl-N-[[2-methyl-4-[6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-270),2-tert-butyl-N-[[4-[6-[[5-(2-hydroxyethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-271),3-isopropoxy-N-[[2-methyl-4-[6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-272),3-isopropoxy-N-[[2-methyl-4-[6-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-ylamino)pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-273),N-[[4-[6-[[5-(2-hydroxyethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamide(I-274),3-tert-butyl-N-[[2-methyl-4-[6-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-275),2-tert-butyl-N-[[4-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-276),N-[[4-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamide(I-277),2-tert-butyl-N-[[2-methyl-4-[6-[(5-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-278),2-tert-butyl-N-[[4-[6-[(5,6-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-279),1-tert-butyl-N-[[4-[6-[(5,6-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrazole-4-carboxamide(I-280),3-tert-butyl-N-[[2-methyl-4-[6-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-281),1-tert-butyl-N-[[4-[6-[(4,5-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrazole-4-carboxamide(I-282),2-tert-butyl-N-[[4-[6-[(4,5-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-283),3-tert-butyl-N-[[4-[6-[(4,5-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrrolidine-1-carboxamide(I-284),2-tert-butyl-N-[[4-[6-[[5-(2-hydroxyethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-285),2-tert-butyl-N-[[2-methyl-4-[6-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-286),3-tert-butoxy-N-[[4-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]azetidine-1-carboxamide(I-287),3-tert-butyl-N-[[4-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrrolidine-1-carboxamide(I-288),2-tert-butyl-5-[[2-methyl-4-[2-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]-4H-pyrrolo[3,4-d]thiazol-6-one(I-289),3-isopropoxy-N-[[4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-290),1-tert-butyl-N-[[2-chloro-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrazole-4-carboxamide(I-291),4-[4-[[4-[4-[[(1-tert-butylpyrazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarboxylicacid (I-292),3-tert-butyl-N-[[4-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-293),3-tert-butoxy-N-[[4-[2-[(1-cyclopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-294),3-tert-butyl-N-[[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-295),3-tert-butyl-N-[[4-[2-[(1-cyclopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-296),3-tert-butyl-N-[[4-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(1-297),3-tert-butyl-N-[[4-[2-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-298),3-isopropoxy-N-[[4-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-299),3-methoxy-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamideacid(I-300),N-[[4-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamide(I-301),3-tert-butoxy-N-[[2-methyl-4-[2-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-302),3-tert-butyl-N-[[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrrolidine-1-carboxamide(I-303),3-tert-butoxy-N-[[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]azetidine-1-carboxamide(I-304),3-tert-butyl-N-[[4-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrrolidine-1-carboxamide(I-305),3-tert-butoxy-N-[[4-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]azetidine-1-carboxamide(I-306),3-(2-fluoroethoxy)-N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-307),3-tert-butyl-N-[[4-[2-[(1-cyclopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]pyrrolidine-1-carboxamide(I-308),1-tert-butyl-5-[[2-methyl-4-[6-[(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl)amino]pyrimidin-4-yl]phenyl]methyl]-6,7-dihydropyrazolo[4,3-c]pyridin-4-one(I-309),1-[[4-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]-4-isobutyl-piperazin-2-one(I-310),3-tert-butyl-N-[[4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-311),N-[[4-[2-[[1-[1,1-dimethyl-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamide(I-312),3-isopropoxy-N-[[4-[2-[[1-[(3S)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-313),3-isopropoxy-N-[[4-[2-[[1-[(3R)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-314),2-tert-butyl-N-[[4-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]thiazole-5-carboxamide(I-315),3-tert-butyl-N-[[4-[2-[[1-[(3S)-pyrrolidin-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-316),3-isopropyl-N-[[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-317),3-tert-butyl-N-[[4-[2-[[1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-318),3-tert-butoxy-N-[[2-(2-methoxyethyl)-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]azetidine-1-carboxamide(I-319),3-tert-butyl-N-[[2-(2-methoxyethyl)-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]pyrrolidine-1-carboxamide(I-320),3-tert-butyl-N-[[4-[2-[(1,5-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(2-hydroxyethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-321),3-tert-butoxy-N-[[4-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)pyrimidin-4-yl]-2-methyl-phenyl]methyl]azetidine-1-carboxamide(I-322),3-tert-butoxy-N-[[4-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)pyrimidin-4-yl]-2-(2-methoxyethyl)phenyl]methyl]azetidine-1-carboxamide(I-323),3-tert-butyl-N-[[4-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)pyrimidin-4-yl]-2-(2-hydroxyethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-324),(3S)-3-tert-butyl-N-[[4-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)pyrimidin-4-yl]-2-(2-methoxyethyl)phenyl]methyl]pyrrolidine-1-carboxamide(I-325),3-isopropoxy-N-[6-[2-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]tetralin-1-yl]azetidine-1-carboxamide(I-326),3-tert-butyl-N-[6-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]tetralin-1-yl]pyrrolidine-1-carboxamide(I-327),3-tert-butyl-N-[2-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-328),N-[2-formyl-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-3-isopropoxy-azetidine-1-carboxamide(I-329),3-tert-butyl-N-[2-[2-[(1-tetrahydropyran-4-ylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-330),3-ethoxy-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-331),3-tert-butoxy-N-[2-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-332),3-isopropoxy-N-[2-[2-[[1-[(3R)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-333),3-tert-butoxy-N-[2-[2-[[1-[(3S)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-334),3-isopropoxy-N-[8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1-benzoxepin-5-yl]azetidine-1-carboxamide(I-335),N-[2-[2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-isopropoxy-azetidine-1-carboxamide(I-336),3-tert-butoxy-N-[2-[2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-337),3-isopropoxy-N-[2-[2-[[1-[(3S)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-338),3-methoxy-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-339),3-isopropyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-340),N-[2-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-isopropyl-pyrrolidine-1-carboxamide(I-341),3-isopropyl-N-[2-[2-[(1-tetrahydropyran-4-ylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-342),3-tert-butoxy-N-[2-[2-[[1-(4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-343),3-isopropyl-N-[2-[2-[[1-[(3R)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-344),3-isopropyl-N-[2-[2-[[1-[(3S)-tetrahydrofuran-3-yl]pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide(I-345),N-[2-(2-hydroxyethyl)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-3-isopropoxy-azetidine-1-carboxamide(I-346),3-tert-butoxy-N-[2-[2-[(1,5-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]azetidine-1-carboxamide(I-347),N-[2-[2-[[1-(3-fluoro-1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-isopropoxy-azetidine-1-carboxamide(I-348),4-isobutyl-1-[[2-methyl-4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]piperazin-2-oneacid(I-349),4-(2,2-dimethylpropyl)-1-[[4-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]piperazin-2-oneacid(I-350),3-isopropoxy-N-[[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]azetidine-1-carboxamide(I-351),3-isopropoxy-N-[7-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]azetidine-1-carboxamide(I-352),N-[[2-chloro-4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamide(I-353),5-tert-butyl-N-[[2-chloro-4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]isoxazole-3-carboxamide(I-354),5-tert-butyl-N-[[4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]-2-(trifluoromethyl)phenyl]methyl]isoxazole-3-carboxamide(I-355),1-tert-butyl-N-[[2-chloro-4-[2-[[1-(1-methylazetidin-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]methyl]pyrazole-4-carboxamide(I-356),2-tert-butyl-N-[[2-methyl-4-[6-[[1-[(3R)-tetrahydrofuran-3-yl]pyrazol-3-yl]amino]pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-357),2-tert-butyl-N-[[2-methyl-4-[6-[[1-(1-methyl-4-piperidyl)pyrazol-3-yl]amino]pyrimidin-4-yl]phenyl]methyl]thiazole-5-carboxamide(I-358),3-tert-butoxy-N-[6-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]tetralin-1-yl]azetidine-1-carboxamide(I-359), andN-[[4-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-phenyl]methyl]-3-isopropoxy-azetidine-1-carboxamideacid(I-360).

General Methods of Providing the Present Compounds

Compounds of the invention are synthesized by an appropriate combinationof generally well known synthetic methods. Techniques useful insynthesizing the compounds of the invention are both readily apparentand accessible to those of skill in the relevant art. The discussionbelow is offered to illustrate certain of the diverse methods availablefor use in assembling the compounds of the invention. However, thediscussion is not intended to define the scope of reactions or reactionsequences that are useful in preparing the compounds of the presentinvention.

In certain embodiments, the present compounds are generally preparedaccording to Scheme A set forth below:

In one aspect, the present invention provides methods for preparingcompounds of formula I, according to the steps depicted in Scheme Aabove wherein each variable is as defined and described herein and eachPG¹ is a suitable protecting group. For compounds having an X^(a) orX^(b) group, X^(a) and X^(b) are defined as a moiety suitable for biarylcoupling with an aryl group of formula E, or a group capable of beingconverted to such a moiety. In some embodiments, X^(a) and X^(b) are thesame. In some embodiments, X^(a) is a group that is converted to X^(b)in order to facilitate coupling with a compound of formula E. In someembodiments, X^(a) is halogen. In some embodiments, X^(b) is halogen, aboronic acid, or a boronic ester. In some embodiments, X^(c) is halogen,a boronic acid, or a boronic ester. It will be appreciated that thereacting partners in a biaryl coupling will be complimentary, andtherefore the identity of X^(b) will depend upon the choice of X^(c) informula E. For example, in some embodiments, X^(b) is a boronic acid orester, and X^(c) is halogen. In other embodiments, X_(c) is a boronicacid or ester, and X^(b) is halogen.

At step S-1, nitrile A is reduced under suitable conditions to formamine B. Suitable nitrile reduction conditions are well known in theart. In some embodiments, the conditions comprise borane.

At step S-2, amine B is protected using a suitable amino protectinggroup. Suitable amino protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, the entirety of which is incorporated herein by reference.Suitable mono-protected amines include those defined herein. In someembodiments, PG¹ is a Boc protecting group.

At step S-3, protected amine C is optionally converted to protectedamine D, depending upon the choice of biaryl couple chemistry asdescribed above. In some embodiments, X^(a) is halogen and is convertedto a boronic ester in step S-3 in order to couple with a compound offormula E. Suitable conditions for the preparation of aryl boronicesters and acids are known in the art. In some embodiments, step S-3comprises bis(pinacolato) diboron and catalytic palladium. In someembodiments, such as when formula E comprises a boronic ester, X^(a) ishalogen and step S-3 is omitted.

At step S-4, protected amine D is coupled with a compound of formula Eto produce biaryl formula F. In some embodiments, step S-4 comprises aSuzuki coupling and X^(b) and X^(a) are selected accordingly. In someembodiments, X^(d) is the same as X^(a). It will be appreciated thatX^(d) will be selected as a moiety capable of undergoing amination instep S-5. In some embodiments, X^(d) is halogen. Methods of carrying outSuzuki couplings are well known in the art and include those describedby March (supra). Suitable conditions for the Suzuki reaction employ apalladium catalyst. In some embodiments, a palladium catalyst isPdCl₂dppf. Step S-4 typically employs a base. In some embodiments, thebase is K₂CO₃.

At step S-5, formula F undergoes amination to form a compound of formulaG. Suitable amination conditions are known in the art and include thosedescribed by March (supra). In certain embodiments, step S-5 comprises apalladium catalyst. In some embodiments, the palladium catalyst isPd₂(dba)₃. In some embodiments, step S-5 comprises a base. In someembodiments, the base is t-BuONa.

At step S-6, the amine group of formula G is deprotected to provideamine H. Suitable conditions for the removal of an amino protectinggroup are known in the art and include those described by Greene(supra).

At step S-7, amine H is coupled with a carboxylic acid to provide acompound of formula I′. Suitable peptide coupling conditions are knownin the art. In some embodiments, step S-7 comprises a peptide couplingreagent selected from a carbodiimide or triazole activating reagent, inthe presence of a base such as DIEA or other bases familiar to oneskilled in the art.

In certain embodiments, each of the aforementioned synthetic steps maybe performed sequentially with isolation of each intermediate performedafter each step. Alternatively, each of steps S-1, S-2, S-3, S-4, S-5,S-6, and S-7 as depicted in Scheme A above, may be performed in a mannerwhereby no isolation of one or more intermediates B, C, D, F, G, or H isperformed.

In certain embodiments, all the steps of the aforementioned synthesismay be performed to prepare the desired final product. In otherembodiments, two, three, four, five, or more sequential steps may beperformed to prepare an intermediate or the desired final product.

In other embodiments, the present compounds are generally preparedaccording to Scheme B set forth below.

In one aspect, the present invention provides methods for preparingcompounds of formula I, according to the steps depicted in Scheme Babove wherein each variable is as defined and described herein.

At step S-8, amine B is coupled with a carboxylic acid to provide acompound of formula K. Suitable peptide coupling conditions are known inthe art. In some embodiments, step S-8 comprises a peptide couplingreagent selected from a carbodiimide or triazole activating reagent, inthe presence of a base such as DIPEA or other bases familiar to oneskilled in the art.

At step S-9, formula K is optionally converted to formula L, dependingupon the choice of biaryl couple chemistry to be performed in step S-10,as described above for Scheme A and step S-3.

At step S-10, formula L is coupled with amine E to provide formula M ina manner similar to that of step S-4 described above in Scheme A.

At step S-11, formula M undergoes amination to form a compound offormula I′. Suitable amination chemistries are known in the art andinclude those described in step S-5, above.

In certain embodiments, each of the aforementioned synthetic steps maybe performed sequentially with isolation of each intermediate performedafter each step. Alternatively, each of steps S-8, S-9, S-10, and S-11as depicted in Scheme B above, may be performed in a manner whereby noisolation of one or more intermediates K, L, or M is performed.

In certain embodiments, all the steps of the aforementioned synthesismay be performed to prepare the desired final product. In otherembodiments, two, three, or four sequential steps may be performed toprepare an intermediate or the desired final product.

Compounds of formula I may also be prepared according to Schemes 1-11 inthe ensuing examples.

Methods of Use

In certain embodiments, compounds of the present invention are for usein medicine. In some embodiments, compounds of the present invention areuseful as kinase inhibitors. In certain embodiments, compounds of thepresent invention are selective inhibitors of Btk. In some embodiments,the present invention provides methods of decreasing Btk enzymaticactivity. Such methods include contacting a Btk with an effective amountof a Btk inhibitor. Therefore, the present invention further providesmethods of inhibiting Btk enzymatic activity by contacting a Btk with aBtk inhibitor of the present invention.

In some embodiments, the present invention provides methods ofdecreasing Btk enzymatic activity. In some embodiments, such methodsinclude contacting a Btk with an effective amount of a Btk inhibitor.Therefore, the present invention further provides methods of inhibitingBtk enzymatic activity by contacting a Btk with a Btk inhibitor of thepresent invention.

Btk enzymatic activity, as used herein, refers to Btk kinase enzymaticactivity. For example, where Btk enzymatic activity is decreased, PIPSbinding and/or phosphorylation of PLCγ is decreased. In someembodiments, the half maximal inhibitory concentration (IC₅₀) of the Btkinhibitor against Btk is less than 1 uM. In some embodiments, the IC₅₀of the Btk inhibitor against Btk is less than 500 nM. In someembodiments, the IC₅₀ of the Btk inhibitor against Btk is less than 100nM. In some embodiments, the IC₅₀ of the Btk inhibitor against Btk isless than 10 nM. In some embodiments, the IC₅₀ of the Btk inhibitoragainst Btk is less than 1 nM. In some embodiments, the IC₅₀ of the Btkinhibitor against Btk is from 0.1 nM to 10 uM. In some embodiments, theIC₅₀ of the Btk inhibitor against Btk is from 0.1 nM to 1 uM. In someembodiments, the IC₅₀ of the Btk inhibitor against Btk is from 0.1 nM to100 nM. In some embodiments, the IC₅₀ of the Btk inhibitor against Btkis from 0.1 nM to 10 nM.

In some embodiments, Btk inhibitors are useful for the treatment ofdiseases and disorders that may be alleviated by inhibiting (i.e.,decreasing) Btk enzymatic activity. By “diseases” is meant diseases ordisease symptoms. Thus, the present invention provides methods oftreating autoimmune disorders, inflammatory disorders, and cancers in asubject in need thereof. Such methods include administering to thesubject a therapeutically effective amount of a Btk inhibitor.

The term “autoimmune disorders” includes diseases or disorders involvinginappropriate immune response against native antigens, such as acutedisseminated encephalomyelitis (ADEM), Addison's disease, alopeciaareata, antiphospholipid antibody syndrome (APS), autoimmune hemolyticanemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease,dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome,Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease,idiopathic thrombocytopenic purpura, lupus erythematosus, mixedconnective tissue disease, multiple sclerosis, myasthenia gravis,pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliarycirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener'sgranulomatosis. The term “inflammatory disorders” includes diseases ordisorders involving acute or chronic inflammation such as allergies,asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease(PID), inflammatory bowel disease (IBD, e.g., Crohn's disease,ulcerative colitis), reperfusion injury, rheumatoid arthritis,transplant rejection, and vasculitis. In some embodiments, the presentinvention provides a method of treating rheumatoid arthritis or lupus.

The term “cancer” includes diseases or disorders involving abnormal cellgrowth and/or proliferation, such as glioma, thyroid carcinoma, breastcarcinoma, lung cancer (e.g. small-cell lung carcinoma, non-small-celllung carcinoma), gastric carcinoma, gastrointestinal stromal tumors,pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma,endometrial carcinoma, prostate carcinoma, renal cell carcinoma,lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acutemyeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia),multiple myeloma, malignant mesothelioma, malignant melanoma, and coloncancer (e.g. microsatellite instability-high colorectal cancer). In someembodiments, the present invention provides a method of treatingleukemia or lymphoma.

The term “subject,” as used herein, refers to a mammal to whom apharmaceutical composition is administered. Exemplary subjects includehumans, as well as veterinary and laboratory animals such as horses,pigs, cattle, dogs, cats, rabbits, rats, mice, and aquatic mammals.

Assays

To develop useful Tec kinase family inhibitors, candidate inhibitorscapable of decreasing Tec kinase family enzymatic activity may beidentified in vitro. The activity of the inhibitor compounds can beassayed utilizing methods known in the art and/or those methodspresented herein.

Compounds that decrease Tec kinase family members' enzymatic activitymay be identified and tested using a biologically active Tec kinasefamily member, either recombinant or naturally occurring. Tec kinasescan be found in native cells, isolated in vitro, or co-expressed orexpressed in a cell. Measuring the reduction in the Tec kinase familymember enzymatic activity in the presence of an inhibitor relative tothe activity in the absence of the inhibitor may be performed using avariety of methods known in the art, such as the POLYGAT-LS assaysdescribed below in the Examples. Other methods for assaying the activityof Btk and other Tec kinases are known in the art. The selection ofappropriate assay methods is well within the capabilities of those ofskill in the art.

Once compounds are identified that are capable of reducing Tec kinasefamily members' enzymatic activity, the compounds may be further testedfor their ability to selectively inhibit a Tec kinase family memberrelative to other enzymes. Inhibition by a compound of the invention ismeasured using standard in vitro or in vivo assays such as those wellknown in the art or as otherwise described herein.

Compounds may be further tested in cell models or animal models fortheir ability to cause a detectable changes in phenotype related to aTec kinase family member activity. In addition to cell cultures, animalmodels may be used to test Tec kinase family member inhibitors for theirability to treat autoimmune disorders, inflammatory disorders, or cancerin an animal model.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of formula I or a compound of formulaI in combination with a pharmaceutically acceptable excipient (e.g.,carrier).

The pharmaceutical compositions include optical isomers, diastereomers,or pharmaceutically acceptable salts of the inhibitors disclosed herein.The compound of formula I included in the pharmaceutical composition maybe covalently attached to a carrier moiety, as described above.Alternatively, the compound of formula I included in the pharmaceuticalcomposition is not covalently linked to a carrier moiety.

A “pharmaceutically acceptable carrier,” as used herein refers topharmaceutical excipients, for example, pharmaceutically,physiologically, acceptable organic or inorganic carrier substancessuitable for enteral or parenteral application that do not deleteriouslyreact with the active agent. Suitable pharmaceutically acceptablecarriers include water, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, and carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, and polyvinylpyrrolidine. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention.

The compounds of the invention can be administered alone or can becoadministered to the subject. Coadministration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). The preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

Formulations

Compounds of the present invention can be prepared and administered in awide variety of oral, parenteral, and topical dosage forms. Thus, thecompounds of the present invention can be administered by injection(e.g. intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally). Also, the compounds describedherein can be administered by inhalation, for example, intranasally.Additionally, the compounds of the present invention can be administeredtransdermally. It is also envisioned that multiple routes ofadministration (e.g., intramuscular, oral, transdermal) can be used toadminister the compounds of the invention. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and one or morecompounds of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substance that may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds of the invention are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampoules areconvenient unit dosages. The compounds of the invention can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in the presentinvention include those described, for example, in PharmaceuticalSciences (17th Ed., Mack Pub. Co., Easton, Pa.) and WO 96/05309, theteachings of both of which are hereby incorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort. Such componentsinclude high molecular weight, anionic mucomimetic polymers, gellingpolysaccharides, and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety for allpurposes.

Effective Dosages

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. For example, when administered in methods to treat cancer, suchcompositions will contain an amount of active ingredient effective toachieve the desired result (e.g. decreasing the number of cancer cellsin a subject).

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated (e.g., the disease responsive to Btk inhibition);presence of other diseases or other health-related problems; kind ofconcurrent treatment; and complications from any disease or treatmentregimen. Other therapeutic regimens or agents can be used in conjunctionwith the methods and compounds of the invention.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of decreasing kinase enzymatic activity as measured, forexample, using the methods described.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring kinase inhibition andadjusting the dosage upwards or downwards, as described above.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention, should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. In some embodiments, thedosage range is 0.001% to 10% w/v. In some embodiments, the dosage rangeis 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

EXAMPLES

The examples below are meant to illustrate certain embodiments of theinvention, and not to limit the scope of the invention.

It will be appreciated that where an Example refers to another Exampleby referring to “Example I-XX”, the reference is to the synthesis of therespective Compound I-XX, or the relevant portion of the synthesis.

Example 1:2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-1)

Preparation of (4-bromo-2-methylphenyl)methanamine

To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20mL), BH₃.THF (45 mL, 45 mmol) was added. The solution was stirred at 0°C. for 1 h and heated to 80° C. for 16 h. Then the mixture was quenchedwith MeOH. After concentrated, the residue was stirred with saturatedHCl/EtOAc solution and filtered. The filter cake was rinsed with ether(20 mL×3) and dried under vacuum to afford(4-bromo-2-methylphenyl)methanamine (3.2 g, yield: 90%) as white solid.ESI-MS (M+H)⁺: 200.1

Preparation of tert-butyl 4-bromo-2-methylbenzylcarbamate

To a solution of (4-bromo-2-methylphenyl)methanamine (1.2 g, 6 mmol) inDCM (30 mL) were added TEA (1.82 g, 18 mmol) and Boc₂O (1.43 g, 6.6mmol). The mixture was stirred at rt for 1 h. After diluted with water(50 mL), the mixture was extracted with DCM (50 mL×2). The combinedorganics were washed with brine (50 mL), dried (Na₂SO₄), filtered andconcentrated to give crude title product (1.7 g, yield 95%) as a whitesolid, which was used directly in the next step without furtherpurification. ESI-MS (M+H)⁺: 300.1.

Preparation of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate

To a solution of tert-butyl 4-bromo-2-methylbenzylcarbamate (1.5 g, 5.0mmol) in 1,4-dioxane (15 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.52 g, 6.0mmol), KOAc (1.75 g, 18 mmol) and Pd(dppf)Cl₂DCM (407 mg, 0.5 mmol)under nitrogen. The mixture was stirred at 100° C. for 2 h. Aftercooling down to rt, the mixture was diluted with water (50 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layer waswashed with brine, dried, concentrated and purified by silica gel column(petroleum ether/EtOAc=10:1) to give tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(1.2 g, yield 69%) as white solid. ESI-MS (M+H)⁺: 348.2. ¹H NMR (400MHz, CDCl₃) δ: 7.61-7.59 (m, 2H), 7.26 (s, 1H), 4.68 (br, 1H), 4.33 (d,J=5.6 Hz, 2H), 2.32 (s, 3H), 1.45 (s, 9H), 1.34 (s, 12H).

Preparation of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate

To a solution of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(3.47 g, 10 mmol) and 2,4-dichloropyrimidine (1.79 g, 12 mmol) in1,4-dioxane (28 mL) and H₂O (7 mL), Pd(dppf)Cl₂DCM (815 mg, 1.0 mmol)and K₂CO₃ (2.76 g, 20 mmol) were added under N₂. The mixture was stirredat 90° C. for 2 h. After cooling to rt, the mixture was diluted with H₂O(80 mL) and extracted with EA (80 mL×2). The organic layers were driedand concentrated. The residue was purified by column chromatography(silica, petroleum ether/EtOAc=5:1 to 2:1) to give tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (2.67 g, yield 80%)as white solid ESI-MS (M+H)⁺: 334.1. ¹H NMR (400 MHz, CDCl₃) δ: 8.12 (d,J=5.2 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.63 (d, J=5.6 Hz,1H), 7.40 (d, J=7.6 Hz, 1H), 4.84 (br, 1H), 4.38 (d, J=5.2 Hz, 1H), 2.41(s, 3H), 1.47 (s, 9H).

Preparation of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

To a solution of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (333 mg, 1.0 mmol)and 1-methyl-pyrazol-4-amine (126 mg, 1.3 mmol) in 1,4-dioxane (5 mL),Pd₂(dba)₃ (92 mg, 0.1 mmol), S-Phos (82 mg, 0.2 mmol) and Cs₂CO₃ (650mg, 2.0 mmol) were added under N₂. The mixture was stirred at 120° C.for 2 h. After cooling to rt, the mixture was diluted with H₂O (40 mL)and extracted with EA (60 mL×2). The organic layers were dried andconcentrated. The residue was purified by column chromatography (silica,petroleum ether/EtOAc=3:1 to 1:1) to give tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate(248 mg, yield 63%) as white solid ESI-MS (M+H)⁺: 395.1. ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=5.2 Hz, 1H), 7.97-7.93 (m, 3H), 7.65 (s, 1H),7.38 (d, J=8.0 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.30 (s, 2H), 3.85 (s,3H), 2.42 (s, 3H), 1.48 (s, 9H).

Preparation of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate(3.94 g, 10.0 mmol) in a solution of HCl in methanol (30 mL, preparedfrom gas HCl) was stirred at rt for 6 h. The solvent was removed and thesolid was rinsed with cold diethyl ether (100 mL). The solid was driedunder vacuum to give4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(2.97 g, yield 90%) as a yellow solid ESI-MS (M+H)⁺: 295.1. ¹H NMR (400MHz, D₂O) δ: 7.98-7.96 (m, 1H), 7.66-7.22 (m, 6H), 4.10 (s, 2H), 3.68(s, 3H), 2.20 (s, 3H).

Preparation of2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

To a mixture of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(200 mg, 0.7 mmol), 2-(tert-butyl)thiazole-5-carboxylic acid (139 mg,0.752 mmol), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.32 g, 0.84 mmol) in N,N-Dimethylformamide (1.58mL, 20.4 mmol) was added N,N-Diisopropylethylamine (0.355 mL, 2.04 mmol)slowly and stirred at room temperature overnight. The mixture wasfiltrate through celite and washed with DMF and purified by prep HPLC togive product,2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a solid (217.5 mg, yield 70%). LCMS: Rt=1.28 min, m/z 462.20. ¹H NMR(300 MHz, DMSO-d6) δ: 9.57 (s, 1H), 9.10 (t, J=5.48 Hz, 1H), 8.46 (d,J=5.29 Hz, 1H), 8.33 (s, 1H), 7.95 (d, J=11.33 Hz, 3H), 7.56 (s, 1H),7.40 (d, J=7.93 Hz, 1H), 7.28 (d, J=5.29 Hz, 1H), 4.50 (d, J=5.29 Hz,2H), 3.65 (s, 3H), 2.42 (s, 3H), 1.39 (s, 9H).

Example 2:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-2)

Synthesis of ethyl thieno[2,3-c]pyridine-2-carboxylate

To a mixture of 3-fluoroisonicotinaldehyde (500 mg, 4.0 mmol) and ethyl2-mercaptoacetate (504 mg, 4.2 mmol) in DMF (7 ml), K₂CO₃ (605 mg, 4.4mmol) was added at 0° C. The mixture was stirred at rt for 12 h. Themixture was poured into water (30 mL), the precipitate was collected anddried to give ethyl thieno[2,3-c]pyridine-2-carboxylate (290 mg, yield:35%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.37 (s, 1H), 8.56(d, J=5.6 Hz, 1H), 8.26 (s, 1H), 7.98 (dd, J=5.2, 0.8 Hz, 1H), 4.39 (q,J=6.8 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

Synthesis of ethyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

A mixture of ethyl thieno[2,3-c]pyridine-2-carboxylate (290 mg, 1.4mmol, 1.0 eq) and Pt₂O (30 mg) in AcOH (5 mL) was stirred at 60° C. for12 h under H₂ atmosphere. After cooling down, the catalyst was filteredout. The resulting filtrate was concentrated under reduced pressure togive ethyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (290mg, yield: 98%) as a yellow oil. ESI-MS (M+1)⁺: 212.1.

Synthesis of 6-tert-butyl 2-ethyl4,5-dihydrothieno[2,3-c]pyridine-2,6(7H)-dicarboxylate

To a mixture of ethyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (290 mg, 1.4 mmol,1.0 equiv), DIPEA (361 mg, 2.8 mmol, 2.0 equiv) in DCM (10 mL), Boc₂O(460 mg, 2.1 mmol, 1.5 equiv) was added. The mixture was stirred at rtfor 2 h. After diluted with DCM (50 mL), the mixture was washed withwater (30 mL), brine (30 mL), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel column(PE:EA=10:1) to give 6-tert-butyl 2-ethyl4,5-dihydrothieno[2,3-c]pyridine-2,6(7H)-dicarboxylate (350 mg, yield:80%) as a colorless oil. ESI-MS (M+H-56)⁺: 256.1. ¹H NMR (400 MHz,CDCl₃) δ: 9.49 (s, 1H), 4.63 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.67 (t,J=5.2 Hz, 2H), 2.70 (t, J=5.2 Hz, 2H), 1.48 (s, 9H), 1.35 (t, J=6.8 Hz,3H).

Synthesis of6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylicacid

To a solution of 6-tert-butyl 2-ethyl4,5-dihydrothieno[2,3-c]pyridine-2,6(7H)-dicarboxylate (350 mg, 1.12mmol, 1.0 equiv) in EtOH (5 mL) and H₂O (5 mL) was added NaOH (180 mg,4.5 mmol, 4.0 equiv). The reaction mixture was stirred at 50° C. for 2h. Then the reaction was cooled to 0° C., and adjusted pH=5 with AcOH.The precipitate was collected and dried to give6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylicacid as a white solid (250 mg, yield: 78%). ESI-MS (M-55)⁺: 228.0

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidewas similar to that of Example I-73, except6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylicacid was substituted for 2-(tert-butyl)thiazole-5-carboxylic acid. Thecrude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobilephase) to get productN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamideas yellow solid (28 mg, yield 41%). ESI-MS (M+H)⁺: 459.9. HPLC: (214 nm:100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J=6.4 Hz, 1H),7.98-7.93 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.42 (d, J=8.0 Hz, 1H),7.22 (d, J=6.4 Hz, 1H), 4.61 (s, 2H), 4.31 (s, 2H), 3.89 (s, 3H), 3.58(t, J=6.0 Hz, 2H), 3.21 (t, J=6.0 Hz, 2H), 2.47 (s, 3H).

Example 3:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(1-3)

Preparation of ethyl 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylate

DMF (1.46 g, 20.0 mmol) was cooled at 0° C. and treated with POCl3 (1.46g, 20.0 mmol) dropwise over 30 min. After addition, 10 mL DCM was addedand stirred for another 1 h. Then dihydro-2H-pyran-4(3H)-one was addedat 0° C. and the solution was allowed to warm up to room temperature for2 h. After neutralized with potassium acetate, the mixture was extractedwith DCM (60 mL×2), dried (Na₂SO₄), filtered and concentrated to give ayellow liquid. The liquid was dissolved in DCM (30 mL) and followed byaddition of ethyl 2-mercaptoacetate (2.40 g, 20.0 mmol) and TEA (4.04 g,40 mmol). Then the solution was heated at reflux for 16 h. The mixturewas concentrated and purified by silica gel column chromatography(petroleum ether/EtOAc=1/4) to give ethyl6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylate as yellow oil (1.95 g,yield 46%). ESI-MS (M+H)⁺: 213.0.

Preparation of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid

A mixture of ethyl 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylate (1.06g, 5.0 mmol) and sodium hydroxide (1.0 g, 25 mmol) in methanol (15 mL)and water (5 mL) was stirred at room temperature for 3 h. After removalof methanol, the residue was diluted with water (15 ml) and the aqueousphase was adjusted to pH=5-6 with 1N HCl. The mixture was extracted withEtOAc (80 mL×2). The organic phase was dried (Na₂SO₄), filtered andconcentrated to give product6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid as a white solid(760 mg, yield 85%). ESI-MS (M+H)⁺: 185.0. ¹H NMR (400 MHz, CD₃OD) δ:7.45 (s, 1H), 4.68 (s, 2H), 3.97 (t, J=5.6 Hz, 2H), 2.90 (t, J=5.6 Hz,2H).

Preparation ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 1, except6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude was purified byprep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to give productN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamideas pale yellow solid (21 mg, yield 43%). ESI-MS (M+H)⁺: 461.0. HPLC:(214 nm: 97%, 254 nm: 92%). ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J=5.2Hz, 1H), 7.98-7.94 (m, 3H), 7.64 (s, 1H), 7.44-7.42 (m, 2H), 7.20 (d,J=5.2 Hz, 1H), 4.68 (s, 2H), 4.61 (s, 2H), 3.98 (d, J=5.6 Hz, 2H), 3.89(s, 3H), 2.90 (d, J=5.6 Hz, 2H), 2.47 (s, 3H).

Example 4:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-4)

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-2-(trifluoromethyl)thiazole-5-carboxamidewas similar to that of Example 1 except2-(trifluoromethyl)thiazole-5-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to giveN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-2-(trifluoromethyl)thiazole-5-carboxamideas a white solid (25 mg, yield 22%). ESI-MS (M+H)⁺: 474.1. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (s, 1H), 8.26(d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (s, 1H),7.56 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 4.56 (s,2H), 3.81 (s, 3H), 2.39 (s, 3H).

Example 5:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-5)

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of Example 1 except4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid was substitutedfor 2-(tert-butyl)thiazole-5-carboxylic acid. The residue was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to giveN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (17 mg, yield 15%). ESI-MS (M+H)⁺: 459.1. HPLC: (214nm: 99%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.25 (d, J=5.6 Hz,1H), 7.89-7.86 (m, 3H), 7.55 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.30 (s,1H), 7.20 (d, J=6.0 Hz, 1H), 4.48 (s, 2H), 3.80 (s, 3H), 2.69 (t, J=6.0Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 2.36 (s, 3H), 1.77-1.70 (m, 4H).

Example 6:5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)picolinamide(I-6)

Synthesis of5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)picolinamidewas similar to that of Example 1 except 5-(tert-butyl)picolinic acid wassubstituted for 2-(tert-butyl)thiazole-5-carboxylic acid. The crudeproduct was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)picolinamideas a yellow solid (35 mg, yield 32%). ESI-MS (M+H)⁺: 456.1. ¹H NMR (400MHz, CDCl₃) δ: 8.58 (d, J=2.4 Hz, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.27 (s,1H), 8.16-8.14 (m, 1H), 7.89-7.84 (m, 4H), 7.54 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.84 (s, 1H), 4.72 (d, J=5.6 Hz, 2H),3.91 (s, 3H), 2.47 (s, 3H), 1.37 (s, 9H).

Example 7:4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(I-7)

To a solution of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(60 mg, 0.2 mmol) and DIPEA (52 mg, 0.4 mmol) in DCM (5 mL) was added4-tert-butylbenzoyl chloride (47 mg, 0.24 mmol). The mixture was stirredat rt for 2 h. After concentrated, the residue was purified by columnchromatography (petroleum ether/EtOAc 1:1 to 1:4) to give compound4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(60 mg, yield: 66%) as a light yellow liquid. ESI-MS (M+H)⁺: 455.1. ¹HNMR (400 MHz, CD₃OD) δ: 8.36 (d, J=5.2 Hz, 1H), 7.93-7.92 (m, 2H), 7.90(d, J=8.0 Hz, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.63 (s, 1H), 7.50 (d, J=8.6Hz, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.15 (d, J=5.2 Hz, 1H), 4.64 (s, 2H),3.88 (s, 3H), 2.47 (s, 3H), 1.34 (s, 9H).

Example 8:3,4-dichloro-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(I-8)

Synthesis of3,4-dichloro-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamidewas similar to that of Example 1, except 3,4-dichlorobenzoic acid wassubstituted for 2-(tert-butyl)thiazole-5-carboxylic acid. The residuewas purified by prep-HPLC (MeCN/H₂O with 0.05% NH₃.H₂O as mobile phase)to give the compound3,4-dichloro-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)benzamide(39 mg, yield: 35%) as a straw yellow solid. ESI-MS (M+H)⁺: 467.1. ¹HNMR (400 MHz, DMSO-d₆) δ: 9.48 (s, 1H), 9.17 (t, J=5.6 Hz, 1H), 8.46 (d,J=5.2 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.96-7.88 (m, 3H),7.79 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.25 (d,J=5.2 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H), 3.82 (s, 3H), 2.43 (s, 3H).

Example 9:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide(I-9)

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamidewas similar to that of Example 1 except4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givecompoundN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide(82 mg, yield: 89%) as a straw yellow solid. ESI-MS (M+H)⁺: 460.0. ¹HNMR (400 MHz, DMSO-d₆) δ: 9.47 (s, 1H), 9.25 (t, J=5.6 Hz, 1H), 8.45 (d,J=5.2 Hz, 1H), 7.94-7.92 (m, 3H), 7.54 (s, 1H), 7.37 (d, J=8.0 Hz, 1H),7.24 (d, J=5.2 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.82 (s, 3H), 2.84 (t,J=5.6 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.42 (s, 3H), 1.83-1.80 (m, 4H).

Example 10:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-2-carboxamide(I-10)

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-2-carboxamidewas similar to that of Example 1, except5,6-dihydro-4H-cyclopenta[d]thiazole-2-carboxylic acid was substitutedfor 2-(tert-butyl)thiazole-5-carboxylic acid. The crude product waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) togiveN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-2-carboxamideas a yellow solid (58 mg, yield 54%). ESI-MS (M+H)⁺: 446.1. HPLC: (214nm: 97%, 254 nm: 99%). ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz,1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.55 (s, 1H),7.44 (d, J=7.6 Hz, 1H), 7.35 (s, 1H), 7.07 (d, J=5.2 Hz, 1H), 6.86 (s,1H), 4.69 (d, J=5.6 Hz, 2H), 3.91 (s, 3H), 2.98 (t, J=6.8 Hz, 2H), 2.85(t, J=7.6 Hz, 2H), 2.57-2.51 (m, 2H), 2.46 (s, 3H).

Example 11:trans-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamide(I-11)

Synthesistrans-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamidewas similar to that of Example 1, excepttrans-4-(trifluoromethyl)cyclohexanecarboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (17 mg, yield 10%). LCMS:Rt=1.33 min, m/z 473.2. 1H NMR (400 MHz, METHANOL-d4) δ 8.34 (d, J=5.77Hz, 1H), 7.99-8.08 (m, 2H), 7.97 (s, 1H), 7.69 (s, 1H), 7.42 (d, J=7.78Hz, 2H), 4.41-4.51 (m, 2H), 3.94 (s, 3H), 2.45 (s, 3H), 1.24-2.39 (m,10H).

Example 12:2-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one(I-12)

Synthesis of methyl 4-(bromomethyl)-2-(tert-butyl)thiazole-5-carboxylate

A mixture of methyl 2-(tert-butyl)-4-methylthiazole-5-carboxylate (90mg, 0.42 mmol), N-bromosuccinimide (83 g, 0.46 mmol) and benzoylperoxide (10 mg, 0.04 mmol) in CCl₄ (10 mL) was stirred at 85° C. for 3h. After concentrated, the residue was diluted with EtOAc (60 mL),washed by saturated aqueous Na₂S₂O₃ (20 mL) and brine (20 mL). Theorganic phase was dried over MgSO₄ and concentrated to give methyl4-(bromomethyl)-2-(tert-butyl)thiazole-5-carboxylate (89 mg, yield: 72%)as a light yellow liquid. ESI-MS (M+H)⁺: 291.9.

Synthesis of methyl2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylate

To a mixture of methyl4-(bromomethyl)-2-(tert-butyl)thiazole-5-carboxylate (89 mg, 0.30 mmol)and4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(202 mg, 0.61 mmol) in MeCN/DMF (12 mL, 5:1) was added K₂CO₃ (126 mg,0.91 mmol). The reaction was kept at 50° C. for 16 h. After filtration,the filtrate was concentrated to give a crude residue which was purifiedby prep-HPLC (MeCN/H₂O with 10 mmol/L NH₄HCO₃ as mobile phase) to givecompound methyl2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylate(98 mg, yield: 64%) as a brown solid. ESI-MS (M+H)⁺: 506.1.

Synthesis of2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylicacid

A mixture of methyl2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylate(86 mg, 0.17 mmol) and NaOH (34 mg, 0.85 mmol) in EtOH (10 mL) wasstirred at 80° C. for 4 h. The resulting solution was concentrated anddiluted with water (6 mL), adjusted to pH=5.0-6.0 with 3N HCl andextracted with EtOAc (30 mL×3). The combined organic phase was driedover MgSO₄ and concentrated to give2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylicacid (82 mg, yield: 98%) as a straw yellow solid. ESI-MS (M+H)⁺: 492.3.

Synthesis of2-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one

To a well-stirred solution of2-(tert-butyl)-4-(((2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)methyl)thiazole-5-carboxylicacid (82 mg, 0.17 mmol) and TEA (116 μL, 0.84 mmol) in DMF/DCM (8 mL,3:1) was added HATU (76 mg, 0.2 mmol) at 0° C. The reaction was kept at0° C. for 2 h and stirred at rt for another 14 h. After diluted withEtOAc (80 mL), the mixture was washed with brine (20 mL×2). The organicphase was dried and concentrated to give a crude residue which waspurified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) togive the compound2-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one(40 mg, yield: 51%) as a straw yellow solid. ESI-MS (M+H)⁺: 474.1. ¹HNMR (400 MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 7.89-7.86 (m, 2H), 7.84(d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.16 (br, 1H),7.06 (d, J=5.2 Hz, 1H), 4.84 (s, 2H), 4.25 (s, 2H), 3.91 (s, 3H), 2.44(s, 3H), 1.47 (s, 9H).

Example 13:2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(I-13)

Synthesis of methyl 3-(bromomethyl)thiophene-2-carboxylate

Synthesis of methyl 3-(bromomethyl)thiophene-2-carboxylate was similarto that of methyl 4-(bromomethyl)-2-(tert-butyl)thiazole-5-carboxylatein Example 12, except methyl 3-methylthiophene-2-carboxylate wassubstituted for methyl 2-(tert-butyl)-4-methylthiazole-5-carboxylate.The organic phase was dried and concentrated to give a crude residuewhich was purified by column chromatography (petroleum ether/EtOAc, 80:1to 30:1) to give compound methyl 3-(bromomethyl)thiophene-2-carboxylate(3.6 g, yield: 59%) as a light yellow liquid. ESI-MS (M+H)⁺: 234.9.

Synthesis of methyl 3-(aminomethyl)thiophene-2-carboxylate

A mixture of methyl 3-(bromomethyl)thiophene-2-carboxylate (1.9 g, 8.1mmol) in 7N NH₃/MeOH (23 mL) and MeOH (20 mL) was stirred at rt for 2 h.After concentrated, the residue was purified by silica gel columnchromatography (DCM/MeOH, 40:1 to 10:1) to give compound methyl3-(aminomethyl)thiophene-2-carboxylate (1.3 g, yield: 94%) as a whitesolid. ESI-MS (M+H)⁺: 172.1.

Synthesis of 4H-thieno[2,3-c]pyrrol-6(5H)-one

A mixture of methyl 3-(aminomethyl)thiophene-2-carboxylate (1.3 mg, 7.6mmol) and K₃CO₃ (1.1 g, 7.6 mmol) in EtOH/MeOH (20 mL, 1:1) was stirredat 70° C. for 16 h. After concentrated, the residue was purified bysilica gel column chromatography (DCM/MeOH, 100:1 to 60:1) to givecompound 4H-thieno[2,3-c]pyrrol-6(5H)-one (580 g, yield: 55%) as a whitesolid. ESI-MS (M+H)⁺: 140.1.

Synthesis of 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one

Br₂ (1.3 g, 8.4 mmol) was added dropwise to the solution of4H-thieno[2,3-c]pyrrol-6(5H)-one (580 mg, 4.2 mmol) in AcOH/MeOH (10 mL,3:2) at 0° C. The mixture was stirred at rt for 40 h. Afterconcentrated, the residue was diluted with EtOAc (160 mL), washed withbrine (60 mL). The organic phase was dried and concentrated to give acrude residue which was purified by column chromatography (DCM/MeOH,100:1 to 80:1) to give the compound2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (616 mg, yield: 68%) as a whitesolid. ESI-MS (M+H)⁺: 217.8.

Synthesis of 2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one

A mixture of 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (202 mg, 0.9mmol), cyclopropyl boronic acid (120 mg, 1.4 mmol), tricyclohexylphosphine (25 mg, 0.1 mmol) and K₃PO₄ (393 mg, 1.9 mmol) in toluene/H₂(17 mL, 16:1) was stirred at 100° C. for 5 min, followed by addition ofPd(OAc)₂ (11 mg, 0.05 mmol). The reaction was kept at 100° C. for 6 h.After concentrated, the residue was purified by silica gel columnchromatography (DCM/MeOH, 100:1 to 80:1) to give the compound2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one (205 mg, yield: 65%) as alight yellow solid. ESI-MS (M+H)⁺: 180.1.

Synthesis of5-(4-bromo-2-methylbenzyl)-2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one

To a mixture of 2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one (150 mg,0.8 mmol) in dry DMF (6 ml) was added 60% NaH (50 mg, 1.3 mmol) at 0° C.The mixture was stirred at rt for 10 min after which4-bromo-1-(bromomethyl)-2-methylbenzene (264 mg, 1.0 mmol) was added.The mixture was stirred at rt for 1 h. Then the reaction was quenched bywater (5 mL) and diluted EtOAc (100 mL), washed by brine (40 mL). Theorganic phase was dried and concentrated to give a crude residue whichwas purified by silica gel column chromatography (petroleum ether/EtOAc,8:1 to 5:1) to give the compound5-(4-bromo-2-methylbenzyl)-2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one(35 mg, yield: 12%) as a light yellow solid. ESI-MS (M+H)⁺: 362.1.

The preparation of 2-chloro-4-methoxypyrimidine

To a solution of 2,4-dichloropyrimidine (41.8 g, 280 mmol) in methanol(900 mL) was added a solution of CH₃ONa (15.2 g, 280 mmol) in 100 mLmethanol at 0° C. The mixture was stirred at rt for overnight. Themixture was concentrated under reduce pressure to give a white solid,which was diluted with water (400 mL) and extracted with ethyl acetate(500 mL×3). The combined organic layer was washed with brine, dried,concentrated to give 2-chloro-4-methoxypyrimidine (40 g, yield: 98%) aswhite solid. ESI-MS (M+H)⁺: 145.0. ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (d,J=5.6 Hz, 1H), 6.68 (s, J=5.6 Hz, 1H), 4.02 (s, 3H).

The preparation of4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To a solution of 2-chloro-4-methoxypyrimidine (36.0 g, 250 mmol),1-methyl-1H-pyrazol-4-amine (32 g, 325 mmol) in 1,4-dioxane (1000 mL)were added Cs₂CO₃ (244 g, 750 mmol), S-phos (4.0 g, 10.0 mmol) andPd₂(dba)₃ (5.0 g, 5.0 mmol) under N₂. The mixture was stirred at 120° C.for 4 h. After cooling down to rt, the mixture was filtered to removethe insoluble matter by silica gel and washed with EA (500 mL). Theorganic phase was concentrated and purified by silica gel column(PE:EA=5:1 to 1:1) to give4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (25.0 g, yield:44%) as gray powder. ESI-MS (M+H)⁺: 206.1. ¹H NMR (400 MHz, CDCl₃) δ:8.06 (d, J=5.6 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 6.15 (d, J=5.6 Hz,1H), 3.97 (s, 3H), 3.88 (s, 3H).

The preparation of4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(25.0 g, 122 mmol) in HBr (200 mL, 48%) was stirred at 100° C. for 2 h.The mixture was concentrated under reduced pressure to give crude2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ol as gray solid. Thesolid was dissolved in POCl₃ (200 mL) and stirred at 100° C. for 16 h.The mixture was concentrated under reduced pressure to remove excessPOCl₃ and the residue was purified by silica gel column (PE:EA=5:1 to2:1) and crystallized from EtOAc to give4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (18.0 g, yield:68% for 2 steps) as white powder. ESI-MS (M+H)⁺: 210.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.29 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 6.75 (d,J=5.2 Hz, 1H), 3.89 (s, 3H).

Synthesis of2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one

Synthesis of2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-onewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate in Example 1. Theresidue was purified by prep-HPLC (MeCN/H₂O with 10 mmol/L NH₄HCO₃ asmobile phase) to give the compound2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(4 mg, yield: 9%) as a light yellow solid. ESI-MS (M+H)⁺: 457.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.42 (d, J=4.8 Hz, 1H), 7.88 (s, 1H), 7.85 (s, 1H),7.82 (d, J=7.6 Hz, 1H), 7.55 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.06 (d,J=4.8 Hz, 1H), 6.90 (s, 1H), 6.66 (s, 1H), 4.79 (s, 2H), 4.07 (s, 2H),3.91 (s, 3H), 2.42 (s, 3H), 2.16-2.10 (m, 1H), 1.11-1.06 (m, 2H),0.82-0.78 (m, 2H).

Example 14:4-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-14)

Synthesis of 5-tert-butyl 2-ethyl4-methyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate

Synthesis of 5-tert-butyl 2-ethyl4-methyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate wassimilar to that of ethyl 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylatein Example 3, except tert-butyl 2-methyl-4-oxopiperidine-1-carboxylatewas substituted for dihydro-2H-pyran-4(3H)-one. The mixture was purifiedby column chromatography (silica, petroleum ether/EtOAc=8:1) to giveproduct (336 mg, yield: 44%) as a white liquid. ESI-MS (M+H-56)⁺: 270.1.

Synthesis of5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid

Synthesis of5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid was similar to that of6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid in Example 3. Thecrude product (240 mg, yield: 55%, white solid) was used in next stepwithout further purification. ESI-MS (M+H-56)⁺: 242.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.37 (s, 1H), 4.72-4.67 (m, 1H), 3.95-3.91 (m, 0.5H),3.73-3.66 (m, 0.5H), 2.99-2.93 (m, 1H), 2.78-2.49 (m, 2H), 1.40-1.39 (m,9H), 1.35 (d, J=6.8 Hz, 1.5H), 1.26 (d, J=6.8 Hz, 1.5H).

Synthesis of4-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

Synthesis of4-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidewas similar to that of Example I-73, except5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid was substituted for 2-(tert-butyl)thiazole-5-carboxylic acid. Theresidue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give4-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamideas a white solid (58 mg, yield: 77%). ESI-MS (M+H)⁺: 474.1. HPLC:(214nm: 97%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.48 (s, 1H),8.84-8.78 (m, 1H), 8.46-8.44 (m, 1H), 7.95-7.92 (m, 3H), 7.64 (s, 0.5),7.54-7.53 (m, 1H), 7.52 (s, 0.5H), 7.39-7.36 (m, 1H), 7.25 (d, J=5.2 Hz,1H), 4.48-4.46 (m, 2H), 3.82 (s, 3H), 3.81-3.71 (m, 1H), 3.23-3.09 (m,1H), 2.92-2.61 (m, 2H), 2.41 (s, 3H), 2.39-2.31 (m, 1H), 1.28 (d, J=6.8Hz, 1.5H), 1.15 (d, J=6.4 Hz, 1.5H).

Example 15:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxamide(I-15)

Synthesis of ethyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate

Synthesis of ethyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate wassimilar to that of ethyl 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylatein Example 3, except dihydro-2H-pyran-3(4H)-one was substituted fordihydro-2H-pyran-4(3H)-one. The residue was purified by columnchromatography (silica, petroleum ether/EtOAc=8:1) to give product ethyl6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate (319 mg, yield: 30%) asa white liquid. ESI-MS (M+H)⁺: 213.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.26(s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.17 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.08-2.02 (m, 2H), 1.35 (t, J=6.8 Hz, 3H).

Synthesis of 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid

Synthesis of 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid wassimilar to that of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acidin Example 3. Crude product6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid (225 mg, yield: 82%,white solid), which was used in next step without further purification.ESI-MS (M+H)⁺: 185.0.

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxamide

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxamidewas similar to that of Example 1, except6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxamideas a white solid (44 mg, yield: 46%). ESI-MS (M+H)⁺: 461.1. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.47 (s, 1H),8.86-8.83 (m, 1H), 8.45 (d, J=5.2 Hz, 1H), 7.95-7.92 (m, 3H), 7.54 (s,1H), 7.40-7.36 (m, 2H), 7.25 (d, J=5.2 Hz, 1H), 4.47 (d, J=5.2 Hz, 2H),4.13-4.11 (m, 2H), 3.82 (s, 3H), 2.74-2.71 (m, 2H), 2.41 (s, 3H),1.98-1.93 (m, 2H).

Example 16:1-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-4-carboxamide(I-16)

Synthesis of1-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-4-carboxamidewas similar to that of Example 1, except 1-methylpiperidine-4-carboxylicacid was substituted for 2-(tert-butyl)thiazole-5-carboxylic acid. Thecrude was filtrate through celite and washed with DMF and purified byprep HPLC to give product as a solid (118 mg, yield: 83%). LCMS:Rt=0.75, m/z 420.3. 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 8.32-8.57(m, 2H), 7.78-8.11 (m, 3H), 7.58 (br. s., 1H), 7.11-7.42 (m, 2H), 4.32(d, J=5.52 Hz, 2H), 3.82 (s, 3H), 2.61-3.71 (m, 6H), 2.54 (s, 3H), 2.37(s, 3H), 1.56-2.14 (m, 3H).

Example 17:cis-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamide(I-17)

Synthesis ofcis-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)cyclohexanecarboxamidewas similar to that of Example 1, exceptcis-4-(trifluoromethyl)cyclohexanecarboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude was purified by prepHPLC to give product as a solid (154 mg, yield:96%). LCMS: Rt=1.32 min,m/z 473.3. 1H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 8.45 (d, J=5.27 Hz,1H), 8.24 (s, 1H), 7.82-8.00 (m, 3H), 7.55 (br. s., 1H), 7.32 (d, J=7.78Hz, 1H), 7.26 (d, J=5.27 Hz, 1H), 4.31 (d, J=5.52 Hz, 2H), 3.80 (s, 3H),2.54-2.74 (m, 1H), 2.37 (s, 3H), 1.11-2.29 (m, 9H).

Example 18.5-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-4-carboxamide(I-18)

Synthesis of5-methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-4-carboxamidewas similar to that of Example 1, except 5-methylisoxazole-4-carboxylicacid was substituted for 2-(tert-butyl)thiazole-5-carboxylic acid. Thecrude was purified by prep HPLC to give product as a solid (62.1 mg,yield: 40%). LCMS: Rt=1.24 min, m/z 404.20. 1H NMR (300 MHz, DMSO-d6) δ:9.49 (s, 1H), 8.46 (d, J=5.29 Hz, 1H), 7.94 (d, J=7.55 Hz, 3H), 7.55 (s,1H), 7.33 (d, J=8.31 Hz, 1H), 7.25 (d, J=5.29 Hz, 1H), 4.43 (s, 2H),3.83 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H).

Example 19:N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)piperidine-1-carboxamide(I-19)

Synthesis ofN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)piperidine-1-carboxamide

To a solution of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(80 mg, 0.24 mmol, 1.0 equiv) in DMF (2 mL) was added TEA (48 mg, 0.48mmol, 2.0 equiv), the mixture was stirred at rt for 10 min. Then CDI (39mg, 0.24 mmol, 1.0 eq) was added and the reaction mixture was stirred atrt for 1 h before 4-(trifluoromethyl)piperidine (48 mg, 0.48 mmol, 2.0eq) was added. The mixture was stirred at room temperature for another12 h. The mixture was purified by prep-HPLC (Gradient: 5% B increase to95% B, A: 0.5% NH₃ in water, B: CH₃CN) to giveN-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)piperidine-1-carboxamide(68 mg, yield: 52%) as a yellow solid. ESI-MS (M+H)⁺:474.2. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.86-7.82 (m, 3H), 7.53 (s, 1H),7.36 (d, J=7.6 Hz, 1H), 7.06-7.05 (m, 2H), 4.67 (t, J=5.2 Hz, 1H), 4.47(d, J=5.6 Hz, 2H), 4.10-4.06 (m, 2H), 3.90 (s, 3H), 2.85-2.78 (m, 2H),2.43 (s, 3H), 2.22-2.16 (m, 1H), 1.91-1.88 (m, 2H), 1.61-1.51 (m, 2H).

Example 20:4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-1-carboxamide(I-20)

Synthesis of 4-(tert-butyl)piperidine

To a mixture of 4-(tert-butyl)pyridine (270 mg, 2 mmol, 1.0 equiv) inAcOH (5 mL) was added PtO₂ (27 mg, 10%). The mixture was stirred at 50°C. for 12 h under hydrogen atmosphere. The catalyst was filtered out andthe resulting filtrate was concentrated to give 4-(tert-butyl)piperidine(130 mg, yield: 48%) as a yellow oil. ESI-MS (M+H): 142.2.

Synthesis of4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-1-carboxamide

Synthesis of4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-1-carboxamidewas similar to that of Example 19, except 4-(tert-butyl)-piperidine wassubstituted for 4-(trifluoromethyl)piperidine. The mixture was purifiedby prep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B:CH₃CN) to give4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperidine-1-carboxamide(73 mg, yield: 65%) as a white solid. ESI-MS (M+H)⁺:462.3. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.88 (s, 1H), 7.84-7.82 (m, 2H),7.55 (s, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.87 (s,1H), 4.61 (t, J=4.4 Hz, 1H), 4.48 (d, J=5.2 Hz, 2H), 4.03-4.00 (m, 2H),3.91 (s, 3H), 2.76-2.71 (m, 2H), 2.43 (s, 3H), 1.71-1.68 (m, 2H),1.24-1.14 (m, 3H), 0.86 (s, 9H).

Example 21:3-isopropoxy-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-21)

4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (prepared in Example 1) (200 mg, 0.7 mmol), 3-isopropoxyazetidine (113 mg, 0.747 mmol), and N,N-carbonyldiimidazole (0.110 g,0.679 mmol) in N,N-dimethylformamide (1.58 mL, 20.4 mmol) was addedN,N-diisopropylethylamine (0.473 mL, 2.72 mmol) slowly and stirred atroom temperature overnight. The mixture was filtrate through celite andwashed with DMF and purified by prep HPLC to give product as a solid (82mg, yield: 30%). LCMS: Rt=1.05 min, m/z 436.3. 1H NMR (400 MHz, DMSO-d6)δ: 9.48 (s, 1H), 8.45 (d, J=5.02 Hz, 1H), 7.92 (s, 3H), 7.55 (br. s.,1H), 7.35 (d, J=8.53 Hz, 1H), 7.25 (d, J=5.27 Hz, 1H), 6.84 (s, 1H),4.15-4.48 (m, 3H), 3.90-4.13 (m, 2H), 3.83 (s, 3H), 3.46-3.69 (m, 3H),2.36 (s, 3H), 1.08 (d, J=6.27 Hz, 6H).

Example 21a:3-((2-d-propan-2-yl)oxy)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

To a solution of N,N-carbonyldiimidazole (66.1 mg, 0.4077 mmol) intetrahydrofuran (5 mL, 60 mmol) was added4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(120.0 mg, 0.4077 mmol) and triethylamine (0.17 mL, 1.223 mmol). Themixture was stirred at RT for 2 h. 3-((2-d-propan-2-yl)oxy)azetidinehydrochloride (124.4 mg, 0.8153 mmol) was then added. The reactionmixture was stirred at rt overnight. The reaction mixture was dilutedwith EtOAc, washed with water. The organic phase was separated, driedand concentrated. The crude was purified by HPLC to give3-((2-D-propan-2-yl)oxy)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a yellow powder (155 mg, TFA salt, yield: 87%). LCMS: RT 1.06 min.;MH+437.2; ¹H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.45 (d, J=5.27 Hz,1H), 7.93 (s, 3H), 7.56 (br. s., 1H), 7.36 (d, J=8.28 Hz, 1H), 7.26 (d,J=5.27 Hz, 1H), 6.85 (t, J=5.27 Hz, 1H), 4.27-4.38 (m, 1H), 4.23 (d,J=4.77 Hz, 2H), 3.98-4.09 (m, 2H), 3.83 (s, 3H), 3.62 (dd, J=4.64, 8.66Hz, 2H), 2.37 (s, 3H), 1.07 (s, 6H).

Example 21b:3-isopropoxy-N-(2-methyl-4-(2-((1-d₃-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide 1.Synthesis of 1-(d₃-methyl-1H-pyrazol-4-amine

A mixture of 4-nitro-1H-pyrazole (5.0 g, 44 mmol) and d₆-dimethylsulfate (10.0 g, 75.7 mmol) in 1 M solution of NaOH in water (50.0 mL)was heated at 35° C. overnight. The solid formed was filtered, washedwith water, and dried (Na₂SO₄) to give 1-d₃-methyl-4-nitro-1H-pyrazoleas a white crystal (3.9 g, yield: 68%). LCMS: RT 0.36 min.; MH+131.1; ¹HNMR (400 MHz, DMSO-d6) δ: 8.84 (s, 1H), 8.23 (s, 1H).

A solution of 1-d₃-methyl-4-nitro-1H-pyrazole (3.9 g, 30 mmol) in EtOH(50.0 mL) was degassed with nitrogen, followed by the addition of 10%palladium on carbon (0.32 g, 0.30 mmol). The mixture was placed under anatmosphere of H₂ and stirred at rt for 2 h. The mixture was filtered andthe filtrate was concentrated in vacuo to give1-(d₃-methyl-1H-pyrazol-4-amine as an oil (2.9 g, yield: 96%) which wasused in the next step without further purification.

2. Synthesis ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

To solution of N,N-carbonyldiimidazole (1.20 g, 7.40 mmol) in THF (100mL) was added a solution of(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)methanamine hydrochloride(2.0 g, 7.40 mmol) and Et₃N (1.0 mL, 7.40 mmol). The mixture was stirredat rt for 12 h, followed by the addition of 3-isopropoxyazetidinehydrochloride (1.12 g, 7.40 mmol) and Et₃N (2.1 mL, 14.8 mmol), and thenstirred at rt for 12 h. The solvent was removed in vacuo to afford thecrude which was purified by silica gel chromatography (EtOAc/heptanegradient) to giveN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamideas a white powder (1.68 g, yield: 60%). LCMS: RT 1.40 min.; MH+375.1; ¹HNMR (400 MHz, DMSO-d6) δ: 9.06 (d, J=0.75 Hz, 1H), 8.28 (s, 1H),7.99-8.13 (m, 2H), 7.36 (d, J=8.53 Hz, 1H), 6.87 (t, J=5.77 Hz, 1H),4.16-4.41 (m, 3H), 4.04 (dd, J=6.78, 8.53 Hz, 2H), 3.51-3.69 (m, 3H),2.36 (s, 3H), 1.08 (d, J=6.27 Hz, 6H).

A mixture ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(150 mg, 0.40 mmol) and 1-methyl-d3-1H-pyrazol-4-amine (52 mg, 0.52mmol) in PhCH₃ (4 mL) was degassed with nitrogen for 5 min, then2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (16 mg, 0.04 mmol) andtris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol) and sodiumtert-butoxide (77 mg, 0.80 mmol) were added and degassed for another 5min, and the reaction was heated in a sealed tube at 100° C. for 1 h.The reaction was then cooled to rt, diluted with EtOAc, and washed withwater and the organic phase was separated, dried (Na₂SO₄), andconcentrated in vacuo to afford the crude which was purified by HPLC togive3-isopropoxy-N-(2-methyl-4-(2-((1-d₃-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a light yellow powder (78 mg, yield: 43%). LCMS: RT 1.05 min.;MH+439.1; ¹H NMR (400 MHz, DMSO-d6) δ: 9.48 (s, 1H), 8.45 (d, J=5.02 Hz,1H), 7.92 (s, 3H), 7.55 (br. s., 1H), 7.35 (d, J=8.28 Hz, 1H), 7.25 (d,J=5.27 Hz, 1H), 6.84 (t, J=5.65 Hz, 1H), 4.27-4.37 (m, 1H), 4.23 (d,J=5.52 Hz, 2H), 3.99-4.09 (m, 2H), 3.51-3.68 (m, 3H), 2.37 (s, 3H), 1.08(d, J=6.02 Hz, 6H).

Example 21c:3-(1,1,1,3,3,3-d6)isopropoxy-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide 1.Synthesis of 3-(1,1,1,3,3,3-d6)isopropoxyazetidine Hydrochloride

Sodium hydride (1.4 g, 35 mmol) was added to a solution of tert-butyl3-hydroxyazetidine-1-carboxylate (2.0 g, 12 mmol) in DMF (50 mL, 600mmol) and stirred at rt for 3 h before 2-bromopropane-1,1,1,3,3,3-d6(1.6 mL, 2.2 g, 17 mmol) was added and heated at 80° C. for 12 h. LC-MSshowed the formation of the desired product (1.45 min, very weak at 214nM and no absorption at 254 nM, ES+/166.2(M-Boc), 244.1(M+Na),267.2(M+2Na), and 465.4(2M+Na)) and remaining starting material (0.84min, ES+/369.2(2M+Na)). Another portion of 2-bromopropane-1,1,1,3,3,3-d6(1.6 mL, 2.2 g, 17 mmol) was added and the reaction was heated for 3 huntil reaction was shown to be completed by LCMS. The reaction wascooled down to rt, and diluted with diethyl ether and water. The organicphase was separated, dried (MgSO₄), concentrated in vacuo and purifiedby silica gel chromatography (EtOAc/Heptane) to give the product as acolorless liquid. 1H NMR (400 MHz, CDCl₃) δ: 1.43 (s, 9H), 3.80 (d,J=4.52 Hz, 2H), 3.88-3.97 (m, 1H), 4.12 (s, 2H), 4.46-4.62 (m, 1H).

To a solution of 3-(1,1,1,3,3,3-d6)isopropoxyazetidine-1 (2.5 g, 11mmol) in 1,4-dioxane (50 mL, 600 mmol) was added a solution of 4 M ofHCl in 1,4-Dioxane (12 mL, 46 mmol) and stirred for 12 h. The solventwas removed and the residue was triturated with diethyl ether to afforda solid which was filtered, washed with diethyl ether and dried to givethe product as a white solid (1.5 g, yield: 84% as HCl salt). 1H NMR(400 MHz, DMSO-d6) δ: 3.60 (s, 1H) 3.66-3.82 (m, 2H) 4.09 (dd, J=11.55,6.78 Hz, 2H) 4.40 (quin, J=6.46 Hz, 1H) 9.17 (br. s., 1H).

2. Synthesis of3-(1,1,1,3,3,3-d6)isopropoxy-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

To a solution of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (0.2 g, 0.6 mmol) and DIEA (0.53 mL, 3.0 mmol) in DMF (10mL, 100 mmol) was added dropwise to a solution of CDI (0.11 g, 0.66mmol) in DMF (2 mL, 20 mmol) at rt. To the solution was added3-(1,1,1,3,3,3-d6)isopropoxyazetidine (0.081 g, 0.66 mmol) HCl salt andstirred at rt for 48 h. The reaction was diluted with water andextracted with EtOAc, dried (MgSO₄), and concentrated in vacuo to affordthe crude which was purified with prep HPLC (CH₃CN/H₂O with 0.05% TFA asmobile phase) to give the desired product as a yellow solid (80 mg,yield: 30% as TFA salt). MS ES+/442.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.46(s, 1H) 8.45 (d, J=5.02 Hz, 1H) 7.92 (s, 3H) 7.55 (br. s., 1H) 7.35 (d,J=8.03 Hz, 1H) 7.24 (d, J=5.02 Hz, 1H) 6.84 (t, J=5.77 Hz, 1H) 4.27-4.38(m, 1H) 4.23 (d, J=5.52 Hz, 2H) 4.00-4.09 (m, 2H) 3.83 (s, 3H) 3.62 (dd,J=8.78, 4.52 Hz, 2H) 3.56 (s, 1H) 2.37 (s, 3H).

Example 22:1-(bicyclo[2.2.2]octan-1-yl)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)urea(I-22)

Synthesis of1-(bicyclo[2.2.2]octan-1-yl)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)ureawas similar to that of Example 19, except bicyclo[2.2.2]octan-1-aminewas substituted for 4-(trifluoromethyl)piperidine. The mixture wasfiltrate through celite and washed with DMF and purified by prep HPLC togive product as a solid (17 mg, yield: 6%). LCMS: Rt=1.32 min, m/z446.2. 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 8.45 (d, J=5.27 Hz,1H), 7.93 (br. s., 3H), 7.55 (br. s., 1H), 7.33 (d, J=8.03 Hz, 1H), 7.25(d, J=5.27 Hz, 1H), 4.19 (br. s., 2H), 3.82 (s, 3H), 2.35 (s, 3H), 1.73(d, J=11.55 Hz, 6H), 1.58 (d, J=7.28 Hz, 6H), 1.49 (br. s., 1H).

Example 23:4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazine-1-carboxamide(I-23)

Synthesis of4-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazine-1-carboxamidewas similar to that of Example 19, except 1-(tert-butyl)piperazine wassubstituted for 4-(trifluoromethyl)piperidine. The mixture was filtratethrough celite and washed with DMF and purified by prep HPLC to giveproduct as a solid (39.7 mg, yield: 10%). LCMS: Rt=0.8 min, m/z 463.3.1H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1H), 8.46 (d, J=5.27 Hz, 1H),7.81-8.02 (m, 3H), 7.03-7.51 (m, 3H), 4.30 (d, J=5.27 Hz, 2H), 4.21 (d,J=13.80 Hz, 2H), 3.38-3.73 (m, 2H), 2.81-3.24 (m, 4H), 2.26-2.44 (m,3H), 1.09-1.43 (m, 9H).

Example 24:2-isopropyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)morpholine-4-carboxamide(I-24)

Synthesis of2-isopropyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)morpholine-4-carboxamidewas similar to that of Example 19, except 2-isopropylmorpholine wassubstituted for 4-(trifluoromethyl)piperidine. The mixture was filtratethrough celite and washed with DMF and purified by prep HPLC to giveproduct as a solid (69 mg, yield: 20%). LCMS: Rt=1.17 min, m/z 450.3. 1HNMR (400 MHz, DMSO-d6) δ: 9.48 (s, 1H), 8.45 (d, J=5.27 Hz, 1H), 7.92(s, 3H), 7.56 (br. s., 1H), 7.35 (d, J=8.28 Hz, 1H), 7.25 (d, J=5.27 Hz,1H), 7.08 (t, J=5.27 Hz, 1H), 4.29 (d, J=5.02 Hz, 2H), 3.70-4.03 (m,6H), 3.41 (d, J=2.51 Hz, 1H), 2.90-3.08 (m, 1H), 2.69-2.88 (m, 1H),2.52-2.62 (m, 1H), 2.38 (s, 3H), 1.64 (qd, J=6.78, 13.55 Hz, 1H), 0.91(dd, J=6.78, 10.54 Hz, 6H).

Example 25:2-(tert-butyl)-N-(2-methyl-4-(2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-25)

Synthesis ofN-(4-bromo-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

A mixture of 2-(tert-butyl)thiazole-5-carboxylic acid (185 mg, 1.0mmol), HBTU (455 mg, 1.2 mmol) and DIPEA (387 mg, 3.0 mmol) in DMF (5mL) was stirred at rt for 15 min. Then(4-bromo-2-methylphenyl)methanamine (300 mg, 1.5 mmol) was added. Theresulting mixture was stirred at rt for 16 h. After diluted with water(40 mL), the mixture was extracted with EtOAc (80 mL×2). The organicphase was concentrated and the residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=10:1-4:1) to giveN-(4-bromo-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide (220 mg,yield: 60%) as a yellow solid. ESI-MS (M+H)⁺: 367.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.20 (s, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.32 (dd, J=8.0, 1.6 Hz,1H), 7.17 (d, J=8.4 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 2.34 (s, 3H), 1.47(s, 9H).

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiazole-5-carboxamide

A mixture ofN-(4-bromo-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide (220 mg,0.6 mmol), KOAc (176 mg, 1.8 mmol) and Pd(dppf)Cl₂DCM (130 mg, 0.06mmol), bis(pinacolato)diboron (168 mg, 0.66 mmol) in dry 1,4-dioxane (6mL) was stirred at 100° C. for 16 h under nitrogen. After cooling downto rt, the mixture was diluted with water (20 mL) and extracted withethyl acetate (50 mL×2). The combined organic layer was washed withbrine, dried, concentrated and purified by silica gel column (petroleumether/EtOAc=4:1) to give2-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiazole-5-carboxamide(188 mg, yield: 75%) as a white solid. ESI-MS (M+H)⁺: 415.0. ¹H NMR (400MHz, CDCl₃) δ: 8.02 (s, 1H), 7.66 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.29(d, J=8.0, 1H), 6.00 (br, 1H), 4.62 (d, J=5.6 Hz, 2H), 2.36 (s, 3H),1.44 (s, 9H), 1.35 (s, 12H).

Synthesis of2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

To a solution of2-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiazole-5-carboxamide(188 mg, 0.45 mmol) in dioxane/H₂O (4:1) (5 mL) was added2,4-dichloropyrimidine (80 mg, 0.54 mmol) followed by Pd(dppf)Cl₂ DCM(44 mg, 0.045 mmol) and K₂CO₃ (124 mg, 0.9 mmol) under nitrogen. Themixture was stirred at 100° C. for 16 h. After cooling to rt, themixture was diluted with water and extracted with EtOAc (60 mL×2). Theorganic layer was washed with brine (40 mL), dried (Na₂SO₄), filteredand concentrated. The residue was purified by column chromatography(silica, petroleum ether/EtOAc=3:1) to give2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a light yellow solid (144 mg, yield: 80%). ESI-MS (M+H)⁺: 401.2

The preparation of2-(tert-butyl)-N-(2-methyl-4-(2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

A mixture of2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(60 mg, 0.15 mmol), 1-methylpiperidin-4-amine (0.3 mmol) and sodiumbicarbonate (26 mg, 0.3 mmol) in DMSO (2 mL) was stirred at 100° C. for4 h. The solid was filtered off and the filtrate was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(40 mg, yield: 56%) as a yellow solid. ESI-MS (M+H)⁺: 479.3. ¹H NMR (400MHz, CD₃OD) δ: 8.16 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.79(d, J=7.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.98 (d, J=5.6 Hz, 1H), 4.50(s, 2H), 3.81-3.79 (m, 1H), 2.82-2.79 (m, 2H), 2.35 (s, 3H), 2.22 (s,3H), 2.19-2.13 (m, 2H), 1.99-1.96 (m, 2H), 1.58-1.50 (m, 2H), 1.35 (s,9H).

Example 26:2-(tert-butyl)-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-26)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 25, except tetrahydro-2H-pyran-4-aminewas substituted for 1-methylpiperidin-4-amine. The crude was purified byprep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) to give thecompound2-(tert-butyl)-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(80 mg, yield: 63%) as a yellow solid. ESI-MS (M+H)⁺: 466.2. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 7.92-7.89 (m, 2H),7.40 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.6 Hz, 1H), 4.61 (s, 2H), 4.10-4.01(m, 1H), 4.01-3.98 (m, 2H), 3.60-3.56 (m, 2H), 2.45 (s, 3H), 2.04-2.01(m, 2H), 1.65-1.61 (m, 2H), 1.46 (s, 9H).

Example 27:(R)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-27)

Synthesis of(R)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 25, except (R)-1-cyclohexylethyl)aminewas substituted for 1-methylpiperidin-4-amine. The crude was purified byprep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) to give thecompound(R)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(35 mg, yield: 52%) as a yellow solid. ESI-MS (M+H)⁺: 492.1. ¹H NMR (400MHz, CD₃OD) δ: 8.13-8.12 (m, 2H), 7.82 (s, 1H), 7.78 (d, J=8.0 Hz, 1H),7.29 (d, J=8.0 Hz, 1H), 6.93 (d, J=5.6 Hz, 1H), 4.50 (s, 2H), 3.95-3.87(m, 1H), 2.35 (s, 3H), 1.80-1.41 (m, 6H), 1.36 (s, 9H), 1.22-0.93 (m,8H).

Example 28:(S)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-28)

Synthesis of(S)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 25, except (S)-1-cyclohexylethyl)aminewas substituted for 1-methylpiperidin-4-amine. The residue was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(S)-2-(tert-butyl)-N-(4-(2-((1-cyclohexylethyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a yellow solid (73 mg, yield: 63%). ESI-MS (M+H)⁺: 491.9. ¹H NMR (400MHz, DMSO-d₆) δ: 9.09 (t, J=4.8 Hz, 1H), 8.34-8.28 (m, 2H), 7.90-7.86(m, 2H), 7.35 (d, J=8.0 Hz, 1H), 7.04 (d, J=4.8 Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.95-3.93 (m, 1H), 2.38 (s, 3H),1.75-1.46 (m, 6H), 1.39 (s, 9H), 1.23-0.97 (m, 8H).

Example 29:2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyridin-4-yl)ethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-291

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyridin-4-yl)ethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 25, except 1-(pyridin-4-yl)ethanamine wassubstituted for 1-methylpiperidin-4-amine. The crude was purified byprep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) to give thecompound2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyridin-4-yl)ethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(40 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 487.2. ¹H NMR (400MHz, CD₃OD) δ: 8.46-8.45 (m, 2H), 8.25 (d, J=5.2 Hz, 1H), 8.23 (s, 1H),7.76-7.75 (m, 2H), 7.52-7.50 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.09 (d,J=5.2 Hz, 1H), 5.18-5.15 (m, 1H), 4.58 (s, 2H), 2.41 (s, 3H), 1.58 (d,J=6.8 Hz, 3H), 1.47 (s, 9H).

Example 30:2-(tert-butyl)-N-(4-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-30)

Synthesis of2-(tert-butyl)-N-(4-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 32, except 4-aminotetrahydro-2H-thiopyran1,1-dioxide was substituted for 1-methylpiperidin-4-amine. The crude waspurified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) togive the compound2-(tert-butyl)-N-(4-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(40 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 514.2. ¹H NMR (400MHz, CD₃OD) δ: 8.31 (d, J=5.6 Hz, 1H), 8.24 (s, 1H), 7.96-7.92 (m, 2H),7.41 (d, J=8.0 Hz, 1H), 7.14 (d, J=5.2 Hz, 1H), 4.61 (s, 2H), 4.25-4.23(m, 1H), 3.26-3.14 (m, 4H), 2.46 (s, 3H), 2.45-2.16 (m, 4H), 2.16 (s,9H).

Example 31:2-(tert-butyl)-N-(4-(2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-31)

Synthesis of2-(tert-butyl)-N-(4-(2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 25, except4-(aminomethyl)tetrahydro-2H-thiopyran 1,1-dioxide was substituted for1-methylpiperidin-4-amine. The crude was purified by prep-HPLC (MeOH/H₂Owith 0.05% NH₃.H₂O as mobile phase) to give the compound2-(tert-butyl)-N-(4-(2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(37 mg, yield: 42%) as a yellow solid. ESI-MS (M+H)⁺: 528.2. ¹HNMR (400MHz, CDCl₃) δ: 8.30 (d, J=5.2 Hz, 1H), 8.05 (s, 1H), 7.82-7.80 (m, 2H),7.03 (d, J=8.0 Hz, 1H), 6.98 (d, J=4.8 Hz, 1H), 6.19-6.18 (m, 1H), 5.42(t, J=5.2 Hz, 1H), 4.66 (d, J=5.2 Hz, 2H), 3.52-3.50 (m, 2H), 3.10-3.07(m, 2H), 3.00-2.93 (m, 2H), 2.44 (s, 3H), 2.24-2.21 (m, 2H), 1.94-1.91(m, 3H), 1.45 (s, 9H).

Example 32:2-(tert-butyl)-N-(2-methyl-4-(2-((pyridin-4-ylmethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-32)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((pyridin-4-ylmethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 25, except pyridin-4-ylmethanamine wassubstituted for 1-methylpiperidin-4-amine. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-((pyridin-4-ylmethyl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a pale yellow solid (40 mg, yield: 72%). ESI-MS (M+H)⁺: 473.1. ¹H NMR(400 MHz, CD₃OD) δ: 8.49 (d, J=5.2 Hz, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.22(s, 1H), 7.81-7.73 (m, 3H), 7.46 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.0 Hz,1H), 7.28 (dd, J=5.6, 1.6 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 4.76 (s, 2H),4.57 (s, 2H), 2.40 (s, 3H), 1.45 (s, 9H).

Example 33: Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-(methylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-33)

A solution of2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(65 mg, 0.16 mmol) in methylamine/THF (2M, 4 mL) was placed in a sealedtube which was heated at 60° C. for 24 h. Then the solvent was removed.The crude was purified through silica gel column chromatography(petroleum ether/EtOAc=1/1) to give2-(tert-butyl)-N-(2-methyl-4-(2-(methylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (30 mg, yield: 47%). ESI-MS (M+H)⁺: 395.9. HPLC: (214nm: 96.80%, 254 nm: 98.36%). ¹H NMR (400 MHz, CD₃OD) δ: 8.16 (d, J=5.6Hz, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.30 (d,J=7.6 Hz, 1H), 6.97 (d, J=5.6 Hz, 1H), 4.51 (s, 2H), 2.91 (s, 3H), 2.35(s, 3H), 1.37 (s, 9H).

Example 34: Synthesis of2-(tert-butyl)-N-(4-(2-(ethylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-34)

Synthesis of2-(tert-butyl)-N-(4-(2-(ethylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 33, except ethylamine was substituted formethyl amine. Obtained2-(tert-butyl)-N-(4-(2-(ethylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(51 mg, yield: 75%) as a white solid. ESI-MS (M+H)⁺: 409.9. HPLC: (214nm: 98.10%, 254 nm: 98.67%). ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (d, J=4.4Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.41 (d,J=8.4 Hz, 1H), 7.09 (d, J=4.4 Hz, 1H), 4.62 (s, 2H), 3.49 (q, J=5.6 Hz,2H), 2.47 (s, 3H), 1.48 (s, 9H), 1.27 (t, J=5.6 Hz, 3H).

Example 35: Synthesis of2-(tert-butyl)-N-(4-(2-(isopropylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-35)

Synthesis of2-(tert-butyl)-N-(4-(2-(isopropylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 33, except isopropylamine was substitutedfor methyl amine.2-(tert-butyl)-N-(4-(2-(isopropylamino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(53 mg, yield: 76%) was obtained as a white solid. ESI-MS (M+H)⁺: 423.9.HPLC: (214 nm: 95.52%, 254 nm: 95.83%). ¹H NMR (400 MHz, CD₃OD) δ: 8.16(d, J=5.2 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.79 (d, J=7.6 Hz, 1H),7.30 (d, J=8.0 Hz, 1H), 6.95 (d, J=5.2 Hz, 1H), 4.51 (s, 2H), 4.14-4.10(m, 1H), 2.37 (s, 3H), 1.37 (s, 9H), 1.18 (d, J=6.4 Hz, 6H).

Example 36:N-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-36)

Preparation of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate

A solution of 4-nitro-1H-pyrazole (1.13 g, 10.00 mmol) and Boc₂O (2.39g, 11.00 mmol) in 20 mL THF was cooled at 0° C. and then DIEA (1.29 g,10.00 mmol) and DMAP (122 mg, 1.0 mmol) was added. The mixture wasstirred at rt for 2 h. After diluted with EtOAc (120 mL), the mixturewas washed with 0.5 N HCl (30 mL) and water (50 mL). The organic phasewas dried (Na₂SO₄), filtered and concentrated to give crude producttert-butyl 4-nitro-1H-pyrazole-1-carboxylate as a yellow solid (2.4 g,yield: 100%) which was used directly in the next step. ESI-MS (M+H-56)⁺:158.0.

Preparation of tert-butyl 4-amino-1H-pyrazole-1-carboxylate

A mixture of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (3.00 g, 14.08mmol) and palladium on charcoal (300 mg, 10% wt) in ethanol (30 mL) wasstirred at rt under H₂ atmosphere (balloon pressure) for 16 h. Thecatalyst was filtered off and the filtrate was concentrated. The residuewas purified by silica gel column chromatography (petroleumether/EtOAc=1/1 with 0.01% TEA) to give product tert-butyl4-amino-1H-pyrazole-1-carboxylate as a white solid (2.30 g, yield: 89%).ESI-MS (M+H)⁺: 129.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.59 (s, 1H), 7.43 (s,1H), 1.63 (s, 9H).

Preparation of tert-butyl4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate

Synthesis of tert-butyl4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/2to 1/1) to give product tert-butyl4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylateas pale yellow solid (90 mg, yield: 31%). ESI-MS (M+H)⁺: 481.0.

Preparation ofN-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

Synthesis ofN-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude product was purified bysilica gel column chromatography (petroleum ether/EtOAc=2/1) to giveproductN-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a pale yellow solid (37 mg, yield: 46%). ESI-MS (M+H)⁺: 447.9. HPLC:(214 nm: 93%, 254 nm: 98%). ¹H NMR (400 MHz, DMSO-d6) δ: 12.47 (s, 1H),9.48 (s, 1H), 9.10 (t, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.33 (s,1H), 7.96-7.93 (m, 3H), 7.60 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.24 (d,J=5.2 Hz, 1H), 4.50 (d, J=5.2 Hz, 2H), 2.41 (s, 3H), 1.39 (s, 9H).

Example 37:2-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-37)

Preparation of 2-(4-nitro-1H-pyrazol-1-yl)ethanol

A mixture of 2-bromoethanol (3.75 g, 30.00 mmol), 4-nitropyrazzole (3.39g, 30.00 mmol) and K₂CO₃ (4.97 g, 36.00 mmol) in acetonitrile (30 mL)was refluxed for 16 h. Then the mixture was filtered and the filtratewas concentrated to dryness to give crude product2-(4-nitro-1H-pyrazol-1-yl)ethanol as a white solid (4.70 g, yield:100%), which was used directly in the next step. ESI-MS (M+H)⁺: 158.0.

Preparation of4-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole

A solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (2.00 g, 12.73 mmol),3,4-dihydro-2H-pyran (1.60 g, 19.10 mmol) and p-toluenesulfonic acid (87mg, 0.51 mmol) in THF (20 mL) was stirred at room temperature for 2 h.Then the mixture was diluted with EtOAc (150 mL), washed with sat.aqueous sodium carbonate (50 mL) and water 60 mL. The organic phase wasdried (Na₂SO₄), filtered and concentrated to give crude product4-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole ascolorless oil (2.00 g, yield: 67%). ESI-MS (M+H)⁺: 242.0.

Preparation of1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-amine

Synthesis of1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-amine wassimilar to that of tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Thecrude was purified by silica gel column chromatography (petroleumether/EtOAc=1/8 to 1/4) to give product1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-amine as a redoil (1.20 g, yield: 69%). ESI-MS (M+H)⁺: 212.0. ¹H NMR (400 MHz, CDCl₃)δ: 7.15 (s, 1H), 7.13 (s, 1H), 4.54-4.52 (m, 1H), 4.22-4.19 (m, 2H),4.04-3.99 (m, 1H), 3.75-3.68 (m, 2H), 3.49-3.44 (m, 1H), 2.87 (br, 2H),1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.58-1.49 (m, 4H).

Preparation of tert-butyl2-methyl-4-(2-((1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(2-((1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/2to 1/1) to give product tert-butyl2-methyl-4-(2-((1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamateas a pale yellow solid (105 mg, yield: 28%). ESI-MS (M+H)⁺: 508.9.

Preparation of2-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.01% ammonia as mobile phase) to give product2-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a yellow solid (56 mg, yield: 56%). ESI-MS (M+H)⁺: 492.0. HPLC: (214nm: 100%, 254 nm: 94%). ¹H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.11(t, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.01 (s, 1H),7.99 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.39 (d, J=7.6 Hz,1H), 7.26 (d, J=5.2 Hz, 1H), 4.92 (br, 1H), 4.50 (d, J=5.2 Hz, 2H), 4.12(t, J=5.2 Hz, 2H), 3.75-3.70 (m, 2H), 2.42 (s, 3H), 1.39 (s, 9H).

Example 38:2-(tert-butyl)-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-38)

Preparation of 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (1.00 g, 9.80 mmol),tetrahydro-2H-pyran-4-ol (1.10 g, 9.80 mmol), triphenyl phosphine (3.34g, 12.74 mmol) in 20 mL dry THF was added DIAD (2.57 g, 12.74 mmol) inone portion under N₂. After addition, the solution was stirred at rt for16 h. Then the mixture was concentrated and purified by silica gelcolumn chromatography (EA/PE=1/4) to give product4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole as a white solid (950mg, yield: 54%). ESI-MS (M+H)⁺: 198.0.

Preparation of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine was similarto that of tert-butyl 4-amino-1H-pyrazole-1-carboxylate. The crudeproduct 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a pink solid(614 mg, yield: 76%) which was used directly in the next step. ESI-MS(M+H)⁺: 168.0. ¹H NMR (400 MHz, CD₃OD) δ: 7.28 (s, 1H), 7.16 (s, 1H),4.29-4.21 (m, 1H), 4.06-4.02 (m, 2H), 3.58-3.52 (m, 2H), 2.02-1.96 (m,4H).

Preparation of tert-butyl2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/2to 1/1) to give product tert-butyl2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamateas a pale yellow solid (75 mg, yield: 33%). ESI-MS (M+H)⁺: 468.1.

Preparation of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.05% TFA as mobile phase) to give product2-(tert-butyl)-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a pale yellow solid (32 mg, yield: 36%). ESI-MS (M+H)⁺: 532.0. HPLC:(214 nm: 97%, 254 nm: 98%). ¹H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H),9.11 (t, J=5.2 Hz, 1H), 8.46 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 8.04 (s,1H), 7.99 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.39 (d, J=8.0Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.39-4.37 (m,1H), 3.97-3.94 (m, 2H), 3.48-3.46 (m, 2H), 2.42 (s, 3H), 2.00-1.90 (m,4H), 1.39 (s, 9H).

Example 39:2-(tert-butyl)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-39)

Synthesis of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole

To a mixture of 4-nitro-1H-pyrazole (113 mg, 1 mmol, 1.0 eq) in CH₃CN (5mL), 1-bromo-2-methoxyethane (138 mg, 1 mmol, 1.0 equiv) and K₂CO₃ (276mg, 2 mmol, 2.0 equiv) was added. The mixture was stirred at 80° C. for4 h. After diluted with EtOAc (100 mL), the mixture was washed withwater (50 mL×2). The organic layer was concentrated and purified bysilica gel column (petroleum ether/EtOAc=10:1) to give1-(2-methoxyethyl)-4-nitro-1H-pyrazole (170 mg, yield: 100%) as acolorless oil. ESI-MS (M+H)⁺: 172.1. ¹H NMR (400 MHz, CDCl₃) δ: 8.23 (s,1H), 8.07 (s, 1H), 4.31 (t, J=5.2 Hz, 2H), 3.74 (t, J=5.2 Hz, 2H), 3.35(s, 3H).

Synthesis of 1-(2-methoxyethyl)-1H-pyrazol-4-amine

Synthesis of 1-(2-methoxyethyl)-1H-pyrazol-4-amine was similar to thatof tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Compound1-(2-methoxyethyl)-1H-pyrazol-4-amine (140 mg, yield: 100%) was obtainedas a red oil. ESI-MS (M+H)⁺: 142.1.

Synthesis of tert-butyl4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture wasconcentrated and purified by prep-HPLC (Gradient: 5% B increase to 95%B, A: 0.5% NH₃ in water, B: CH₃CN) to give tert-butyl4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate(160 mg, yield: 90%) as a yellow solid. ESI-MS (M+H)⁺: 439.3. ¹H NMR(400 MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.85-7.83 (m,2H), 7.60 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H), 7.03(s, 1H), 4.87 (br, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.29 (t, J=5.2 Hz, 2H),3.78 (t, J=5.2 Hz, 2H), 3.35 (s, 3H), 2.41 (s, 3H), 1.47 (s, 9H).

Synthesis of2-(tert-butyl)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(55 mg, yield: 27%) as a yellow solid. ESI-MS (M+H)⁺: 506.1. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.89(s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J=8.0 Hz, 1H),7.06 (d, J=5.2 Hz, 1H), 6.93 (s, 1H), 6.09 (t, J=7.2 Hz, 1H), 4.67 (d,J=5.6 Hz, 2H), 4.28 (t, J=5.6 Hz, 2H), 3.78 (t, J=5.6 Hz, 2H), 3.35 (s,3H), 2.45 (s, 3H), 1.45 (s, 9H).

Example 40:2-(tert-butyl)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-40)

A mixture of2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(100 mg, 0.25 mmol), 1-ethyl-1H-pyrazol-4-amine (28 mg, 0.25 mmol),t-BuONa (72 mg, 0.75 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), S-Phos (25 mg,0.06 mmol) in 5 mL 1,4-dioxane was heated at 100° C. for 1 h undermicrowave and nitrogen. After cooling to rt and diluted with EtOAc (120mL), the mixture was washed with water (60 mL). The organic phase wasdried and concentrated. The residue was purified by pre-TLC(MeOH/DCM=1/20) to give product2-(tert-butyl)-N-(4-(2-((l-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a yellow solid (50 mg, yield: 44%). ESI-MS (M+H)⁺: 476.2. ¹H NMR (400MHz, CDCl₃) δ: 8.43 (d, J=4.4 Hz, 1H), 8.05 (s, 1H), 7.92-7.84 (m, 3H),7.56 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.99 (m,1H), 6.05 (br, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 2.45(s, 3H), 1.52 (t, J=7.2 Hz, 3H), 1.45 (s, 9H).

Example 41:2-(tert-butyl)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-41)

Synthesis of2-(tert-butyl)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 37, except 1-isopropyl-1H-pyrazol-4-aminewas substituted for 1-ethyl-1H-pyrazol-4-amine. The residue was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% ammonia as mobile phase) to giveproduct2-(tert-butyl)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a pale yellow solid (45 mg, yield: 55%). ESI-MS (M+H)⁺: 490.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.39 (d, J=4.8 Hz, 1H), 8.24 (s, 1H), 8.06 (s, 1H),7.99 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.43 (d, J=8.0 Hz,1H), 7.20 (d, J=5.2 Hz, 1H), 4.62 (s, 2H), 4.52-4.48 (m, 1H), 2.47 (s,3H), 1.52 (d, J=6.8 Hz, 6H), 1.46 (s, 9H).

Example 42:N-(4-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-42)

Synthesis of tert-butyl3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate

DIAD (3.92 mL, 19.9 mmmol, 1.5 equiv) was added dropwise to a stirredsolution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol),1-Boc-3-Hydroxyazetidine (2.3 g, 13.27 mmol, 1 equiv) andtriphenylphosphine (5.22 g, 19.9 mmol, 1.5 equiv) in THF (30 mL) placedan ice-bath under N₂. The mixture was stirred at 0° C. for 10 min andallowed to warm to rt and stirred for 16 h. After diluted with EA (100mL), the mixture was washed with water (40 mL), brine (30 mL×2). Thecombined organic layer was dried, concentrated. The crude was purifiedthrough silica gel column chromatography (petroleum ether/EtOAc=1/10) togive tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate aslight yellow solid (3 g, yield: 85%). ESI-MS (M+H-56)⁺: 213.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.28 (s, 1H), 8.16 (s, 1H), 5.07-5.04 (m, 1H),4.44-4.40 (m, 2H), 4.34-4.30 (m, 2H), 1.47 (s, 9H).

Synthesis of tert-butyl3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate

Synthesis of tert-butyl3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate was similar to thatof tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Obtained tert-butyl3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate (1 g, yield: 95%) aspurple red oil. ESI-MS (M+H-56)⁺: 183.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.22(s, 1H), 7.14 (s, 1H), 4.93-4.89 (m, 1H), 4.35-4.31 (m, 2H), 4.25-4.22(m, 2H), 2.94 (br, 2H), 1.45 (s, 9H).

Synthesis of tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Synthesis of tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Purified throughsilica gel column chromatography with (MeOH/DCM=1/20) to give tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate(150 mg, yield: 69%) as a yellow solid. ESI-MS (M+H)⁺: 603.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.45 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.05 (s, 1H),7.88 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=8.0 Hz,1H), 7.10 (d, J=5.6 Hz, 1H), 6.94 (s, 1H), 6.11-6.09 (m, 1H), 5.08-5.01(m, 1H), 4.68 (d, J=5.2 Hz, 2H), 4.42-4.33 (m, 4H), 2.46 (s, 3H), 1.56(s, 9H), 1.45 (s, 9H).

Synthesis ofN-(4-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

To a solution of tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate(150 mg, 0.25 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture wasstirred at rt for 1 h. The solvent was removed. The crude was purifiedthrough prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(4-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a yellow solid (125 mg, yield: 100%). ESI-MS (M+H)⁺: 503.1. HPLC:(214 nm: 97.49%, 254 nm: 98.23%). ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d,J=5.2 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.96 (d, J=8.0Hz, 1H), 7.85 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.6 Hz, 1H),5.45-5.37 (m, 1H), 4.63 (s, 2H), 4.57-4.54 (m, 4H), 2.48 (s, 3H), 1.47(s, 9H).

Example 43:2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-43)

To a solution ofN-(4-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(95 mg, 0.189 mmol) in MeOH (4 mL) were added paraformaldehyde (24 mg,0.757 mmol, 4 equiv), NaBH₃CN (24 mg, 0.378 mmol, 2 equiv) and AcOH(cat.). The mixture was stirred at rt for 16 h. After diluted with EtOAc(80 mL), the mixture was washed with water (20 mL), dried andconcentrated. The crude was purified through prep-TLC (MeOH/DCM=1/15) togive2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (42 mg, yield: 43%). ESI-MS (M+H)⁺: 517.3. HPLC: (214nm: 97.38%, 254 nm: 97.27%). ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d, J=5.6Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.96 (d, J=8.0 Hz,1H), 7.73 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H),5.02-4.95 (m, 1H), 4.63 (s, 2H), 3.89-3.85 (m, 2H), 3.61-3.57 (m, 2H),2.48 (s, 3H), 2.47 (s, 3H), 1.47 (s, 9H).

Example 44: The preparation of3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarboxylicacid (I-44)

Synthesis of3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarboxylicacid was similar to that of Example 37 starting from methyl3-hydroxycyclobutanecarboxylate. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% ammonia as mobile phase) to give product3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarboxylicacid as a pale yellow solid (25 mg, yield: 12%). ESI-MS (M+H)⁺: 546.1.¹H NMR (400 MHz, CD₃OD) δ: 8.35 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 8.09(s, 1H), 8.04 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.46 (d,J=8.0 Hz, 1H), 7.37 (d, J=5.6 Hz, 1H), 5.52-5.47 (m, 1H), 4.62 (s, 2H),3.20-3.16 (m, 1H), 2.91-2.75 (m, 4H), 2.48 (s, 3H), 1.46 (s, 9H).

Example 45:2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-45)

Synthesis of tert-butyl4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of tert-butyl4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate was similar to thatof tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate. Thecrude product was purified through silica gel column chromatography with(petroleum ether/EtOAc=1/10) to give tert-butyl4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate as light yellowsolid (3.2 g, yield: 84%). ESI-MS (M+H-56)⁺: 241.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.17 (s, 1H), 8.08 (s, 1H), 5.00-4.94 (m, 1H), 4.33-4.26 (m,2H), 2.93-2.87 (m, 2H), 2.18-2.15 (m, 2H), 1.96-1.86 (m, 2H), 1.48 (s,9H).

Synthesis of tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was similar to thatof tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Obtained tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.6 g, yield: 95%)as purple oil. ESI-MS (M+H)⁺: 267.2. ¹H NMR (400 MHz, CDCl₃) δ: 7.16 (s,1H), 7.03 (s, 1H), 5.00-4.94 (m, 1H), 4.23-4.14 (m, 2H), 2.89-2.83 (m,2H), 2.08-2.04 (m, 2H), 1.88-1.78 (m, 2H), 1.47 (s, 9H).

Synthesis of tert-butyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of tert-butyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude productwas purified through silica gel column chromatography with(MeOH/DCM=1/25) to give tert-butyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(270 mg, yield: 84%) as a yellow solid. ESI-MS (M+H)⁺: 631.2.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 42. Purified through prep-HPLC (CH₃CN/H₂Owith 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(220 mg, yield: 95%) as a yellow solid. ESI-MS (M+H)⁺: 531.0. HPLC: (214nm: 99.77%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.37 (d, J=5.6 Hz,1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.96 (d, J=8.4 Hz, 1H),7.75 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.29 (d, J=6.0 Hz, 1H), 4.61 (s,2H), 4.57-4.50 (m, 1H), 3.59-3.56 (m, 2H), 3.26-3.19 (m, 2H), 2.47 (s,3H), 2.38-2.23 (m, 4H), 1.46 (s, 9H).

Example 46:2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-46)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 43. Purified through prep-TLC(MeOH/DCM=1/15) to give2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(20 mg, yield: 55%) as a yellow solid. ESI-MS (M+H)⁺: 545.2. HPLC: (214nm: 99.51%, 254 nm: 98.97%). ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J=5.2Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.95 (d, J=8.4 Hz,1H), 7.67 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 4.63(s, 2H), 4.20-4.15 (m, 1H), 3.04-3.01 (m, 2H), 2.48 (s, 3H), 2.35 (s,3H), 2.31-2.26 (m, 2H), 2.19-2.07 (m, 4H), 1.47 (s, 9H).

Example 47: Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-47)

To a solution of2-(tert-butyl)-N-(2-methyl-4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(63 mg, 0.119 mmol) in DCM (5 mL) were added Ms₂O (22 mg, 0.125 mmol,1.05 equiv) and TEA (24 mg, 0.238 mmol, 2 equiv). The mixture wasstirred at rt for 1 h. After diluted with DCM (80 mL), the mixture waswashed with brine (30 mL), dried and concentrated. The crude waspurified through silica gel column chromatography (MeOH/DCM=1/20) togive2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (30 mg, yield: 40%). ESI-MS (M+H)⁺: 609.2. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CDCl₃) δ: 8.44 (d, J=5.2 Hz,1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.85 (d, J=8.0 Hz, 1H),7.57 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 6.95 (s,1H), 6.12 (br, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.30-4.23 (m, 1H), 3.93-3.89(m, 2H), 2.99-2.93 (m, 2H), 2.84 (s, 3H), 2.46 (s, 3H), 2.32-2.27 (m,2H), 2.23-2.13 (m, 2H), 1.45 (s, 9H).

Example 48:cis-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (I-48) andtrans-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (I-49)

Synthesis of methyl 4-(tosyloxy)cyclohexanecarboxylate

To a mixture of methyl 4-hydroxycyclohexanecarboxylate (172 mg, 1 mmol,1.0 equiv) in pyridine (2 mL), TsCl (285 mg, 1.5 mmol, 1.5 equiv) wasadded. The mixture was stirred rt for 12 h. After diluted with EtOAc(100 mL), the mixture was washed with HCl (1 N, 50 mL), water (50 mL).The organic layer was dried and concentrated to give methyl4-(tosyloxy)cyclohexanecarboxylate (326 mg, yield: 100%) as a colorlessoil and used for next step without further purification. ESI-MS (M+Na)⁺:355.1.

Synthesis of methyl 4-(4-nitro-1H-pyrazol-1-yl)cyclohexanecarboxylate

Synthesis of methyl 4-(4-nitro-1H-pyrazol-1-yl)cyclohexanecarboxylatewas similar to that of 2-(4-nitro-1H-pyrazol-1-yl)ethanol. The organiclayer was concentrated and purified by silica gel column (petroleumether/EtOAc=3:1) to give methyl4-(4-nitro-1H-pyrazol-1-yl)cyclohexanecarboxylate (110 mg, yield: 49%)as a colorless oil. ESI-MS (M+H)⁺: 254.1.

Synthesis of methyl 4-(4-amino-1H-pyrazol-1-yl)cyclohexanecarboxylate

Synthesis of methyl 4-(4-amino-1H-pyrazol-1-yl)cyclohexanecarboxylatewas similar to that of tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Thecatalyst was filtered out and the resulting filtrate was concentrated togive target compound methyl4-(4-amino-1H-pyrazol-1-yl)cyclohexanecarboxylate (93 mg, yield: 97%) asa yellow oil. ESI-MS (M+H)⁺: 224.1.

Synthesis of methyl4-(4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate

Synthesis of methyl4-(4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The residue waspurified by prep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% NH₃ inwater, B: CH₃CN) to give methyl4-(4-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate(94 mg, yield: 50%) as a yellow solid. ESI-MS (M+H)⁺: 521.2. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=4.8 Hz, 1H), 7.98 (s, 1H), 7.88-7.83 (m, 2H),7.58 (s, 1H), 7.38-7.31 (m, 1H), 7.07-7.06 (m, 1H), 6.96-6.95 (m, 1H),4.79 (br, 1H), 4.37 (d, J=5.2 Hz, 2H), 4.18-4.09 (m, 1H), 3.71 (s, 3H),2.41 (s, 3H), 2.32-2.17 (m, 3H), 2.10-1.99 (m, 3H), 1.76-1.69 (m, 3H),1.47 (s, 9H).

Synthesis of methyl4-(44(4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate

Synthesis of methyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylatewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive methyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate(40 mg, yield: 38%) as a yellow solid. ESI-MS (M+H)⁺: 588.3.

Synthesis ofcis-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid andtrans-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid

To a mixture of methyl4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate(40 mg, 0.07 mmol, 1.0 equiv) in MeOH (3 mL)/H₂O (1 mL), NaOH (11 mg,0.28 mmol, 4.0 equiv) was added. The mixture was stirred at rt for 12 h.After concentrated and diluted with water (5 mL), the mixture wasacidified to pH=5 with HCl (1 N), the precipitate was collected andpurified by prep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% NH₃ inwater, B: CH₃CN) to givecis-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (9 mg, yield: 23%) andtrans-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (13 mg, yield: 33%) as yellow solid. ESI-MS (M+H)⁺: 574.2.

cis-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid: ¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J=5.2 Hz, 1H), 8.07 (s, 1H),8.04 (s, 1H), 7.80-7.78 (m, 2H), 7.50 (s, 1H), 7.41 (d, J=7.6 Hz, 1H),7.01 (d, J=5.2 Hz, 1H), 4.56 (s, 2H), 4.14-4.05 (m, 1H), 2.64-2.61 (m,1H), 2.41 (s, 3H), 2.24-2.19 (m, 2H), 2.04-1.91 (m, 4H), 1.70-1.62 (m,2H), 1.39 (s, 9H).

trans-4-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid: ¹H NMR (400 MHz, CD₃OD) δ: 8.31 (d, J=5.2 Hz, 1H), 8.02 (s, 1H),7.91 (s, 1H), 7.81 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.35(d, J=8.0 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 4.56 (s, 2H), 4.07-4.00 (m,1H), 2.39 (s, 3H), 2.33-2.26 (m, 1H), 2.23-2.11 (m, 4H), 1.81-1.71 (m,2H), 1.63-1.53 (m, 2H), 1.39 (s, 9H).

Example 49:N-(4-(2-((1-(2-aminoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-50)

Preparation of tert-butyl (2-(4-amino-1H-pyrazol-1-yl)ethyl)carbamate

Synthesis of tert-butyl (2-(4-amino-1H-pyrazol-1-yl)ethyl)carbamate wassimilar to that of tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Thecrude product (470 mg. yield: 98%) was used in the next step withoutfurther purification. ESI-MS (M+H)⁺: 227.1.

Preparation of tert-butyl(2-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethyl)carbamate

Synthesis of tert-butyl(2-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethyl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The residue waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) togive tert-butyl(2-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethyl)carbamateas a white solid (62 mg, yield: 53%). ESI-MS (M+H)⁺: 591.2.

Preparation ofN-(4-(2-((1-(2-aminoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

A mixture of tert-butyl(2-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethyl)carbamate(78 mg, 0.13 mmol) in TFA/DCM (10 mL, 1:1) was stirred at rt for 1 h.Then the solvent was removed. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to giveN-(4-(2-((1-(2-aminoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a yellow solid (36 mg, yield: 56%). ESI-MS (M+H)⁺: 491.1. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J=5.2 Hz,1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.98-7.95 (m, 2H), 7.74 (s, 1H), 7.44(d, J=8.4 Hz, 1H), 7.28-7.26 (m, 1H), 4.61 (s, 2H), 4.44 (t, J=5.6 Hz,2H), 3.44 (t, J=5.6 Hz, 2H), 2.48 (s, 3H), 1.46 (s, 9H).

Example 50:2-(tert-butyl)-N-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-51)

Preparation of tert-butyl4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamateand tert-butyl4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The resultingproduct was purified by column chromatography (petroleum ether/EtOAc=5:1to 1:2) to give tert-butyl4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate(116 mg) and tert-butyl4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamateas a yellow solid (218 mg, yield: 86%). ESI-MS (M+H)⁺: 409.3.

tert-butyl4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate:¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.83(s, 1H), 7.81 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.05 (d, J=5.6 Hz, 1H),6.59 (s, 1H), 4.38 (d, J=5.2 Hz, 2H), 3.85 (s, 3H), 2.41 (s, 3H), 2.27(s, 3H), 1.47 (s, 9H).

tert-butyl4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate:¹H NMR (400 MHz, CDCl₃) δ: 8.37 (d, J=5.2 Hz, 1H), 7.83 (s, 1H), 7.81(s, 1H), 7.69 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H),6.42 (s, 1H), 4.36 (d, J=5.2 Hz, 2H), 3.81 (s, 3H), 2.40 (s, 3H), 2.27(s, 3H), 1.47 (s, 9H).

Preparation of2-(tert-butyl)-N-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 1. The resulting product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(88 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 476.3. ¹H NMR (400MHz, DMSO-d₆) δ: 8.76 (t, J=6.4 Hz, 1H), 8.40 (d, J=4.8 Hz, 1H), 8.30(s, 1H), 7.88-7.83 (m, 3H), 7.72-7.69 (m, 1H), 7.43 (d, J=7.6 Hz, 1H),7.07 (d, J=4.8 Hz, 1H), 4.57 (d, J=5.2 Hz, 2H), 3.84 (s, 3H), 2.59 (s,3H), 2.26 (s, 3H), 1.45 (s, 9H).

Example 51: The preparation of2-(tert-butyl)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-52)

Synthesis of2-(tert-butyl)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 50. The resulting product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(135 mg, yield: 50%) as a yellow solid. ESI-MS (M+H)⁺: 476.3. ¹H NMR(400 MHz, CDCl₃) δ: 8.35 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 7.78 (s, 1H),7.74 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.11 (br,1H), 6.99 (d, J=5.2 Hz, 1H), 6.80 (br, 1H), 4.61 (d, J=5.2 Hz, 2H), 3.73(s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.44 (s, 9H).

Example 52:2-(tert-butyl)-N-(2-methyl-4-(2-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-53)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 50 starting from1,3,5-trimethyl-1H-pyrazol-4-amine. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give ayellow solid (15 mg, yield: 25%). ESI-MS (M+H)⁺: 490.2. HPLC: (214 nm:98.13%, 254 nm: 97.13%). ¹H NMR (400 MHz, CD₃OD) δ: 8.14-8.12 (m, 2H),7.81-7.75 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 7.07 (d, J=5.6 Hz, 1H), 4.48(s, 2H), 3.62 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.34(s, 9H).

Example 53:2-(tert-butyl)-N-(2-methyl-4-(2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-54)

Synthesis of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

A mixture of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (625mg, 2 mmol) and ammonia in methanol (5.73 mL, 40 mmol, 20 eq) in asealed tube was stirred at 50° C. for 2 h. Then the solvent was removed.The crude was purified through silica gel columnchromatography(MeOH/DCM=1/20) to give2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine as a white solid (270mg, yield: 80%).

Synthesis of tert-butyl2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (270mg, 1.61 mmol) in DCM (20 mL) was added Boc₂O (368 mg, 1.69 mmol, 1.05equiv) and TEA (324 mg, 3.2 mmol, 2 equiv). The mixture was stirred atrt for 16 h. After diluted with DCM (20 mL), the mixture was washed withwater (40 mL) and brine (20 mL). The organic layer was dried andconcentrated. The crude was purified through silica gel columnchromatography (petroleum ether/EtOAc=1/3) to give tert-butyl2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate as a whitesolid (380 mg, yield: 88%).

Synthesis of tert-butyl2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

To a solution of tert-butyl2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (380 mg,1.42 mmol) in methanol (20 mL) was added Pd/C (38 mg, 10% wt). Themixture was stirred at rt for 16 h under H₂ atmosphere (balloonpressure). The mixture was filtered through Celite. The filtrate wasconcentrated to give tert-butyl2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate as a whitesolid (330 mg, yield: 90%). ¹H NMR (400 MHz, CDCl₃) δ: 5.41 (s, 1H),4.53 (s, 2H), 3.95 (t, J=5.2 Hz, 2H), 3.83 (t, J=5.2 Hz, 2H), 3.60 (s,2H), 1.48 (s, 9H).

Synthesis of tert-butyl2-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

Synthesis of tert-butyl2-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.Obtained tert-butyl2-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate(140 mg, yield: 60%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ:9.77 (s, 1H), 9.11 (t, J=5.2 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.34 (s,1H), 7.97 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.33(d, J=5.6 Hz, 1H), 6.60 (s, 1H), 4.61 (s, 2H), 4.50 (d, J=5.2 Hz, 2H),3.98 (t, J=5.2 Hz, 2H), 3.82 (t, J=5.2 Hz, 2H), 2.41 (s, 3H), 1.44 (s,9H), 1.39 (s, 9H).

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

To a solution of tert-butyl2-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate(120 mg, 0.2 mmol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixturewas stirred at rt for 1 h. The solvent was removed. The crude wasdissolved in water and adjusted pH to 7-8 with NH₃H₂O. Then the formedsolid was filtered to give2-(tert-butyl)-N-(2-methyl-4-(2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(70 mg, yield: 70%) as a light yellow solid. ESI-MS (M+H)⁺: 502.8. HPLC:(214 nm: 97.70%, 254 nm: 96.52%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s,1H), 9.11 (t, J=5.2 Hz, 1H), 8.44-8.33 (m, 2H), 7.97-7.96 (m, 2H),7.39-7.31 (m, 2H), 6.46 (s, 1H), 4.50 (s, 2H), 3.89-3.87 (m, 4H),3.10-3.08 (s, 2H), 2.36 (s, 3H), 1.39 (s, 9H).

Example 54:2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-55)

Preparation of tert-butyl2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude was purified by pre-TLC (MeOH/DCM=1/20) to give producttert-butyl2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamateas a yellow solid (50 mg, yield: 37%). ESI-MS (M+H)⁺: 449.9.

Preparation of2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.05% ammonia as mobile phase) to give product2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (31 mg, yield: 54%). ESI-MS (M+H)⁺: 516.9. HPLC: (214nm: 100%, 254 nm: 96%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.69 (s, 1H), 9.11(t, J=5.6 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.97 (s, 1H),7.95 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H),6.50 (s, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.96 (t, J=5.6 Hz, 2H), 3.57 (s,2H), 2.82 (t, J=5.6 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.39 (s, 9H).

Example 55:2-(tert-butyl)-N-(4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-56)

Preparation of tert-butyl4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate

A mixture of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (100 mg, 0.30 mmol),5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (50 mg, 0.30mmol), t-BuONa (86 mg, 0.90 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), X-Phos(28 mg, 0.06 mmol) in 5 mL 1,4-dioxane was heated at 100° C. for 2 hunder nitrogen. After cooling to rt and diluted with EtOAc (120 mL), themixture was washed with water (60 mL). The organic phase was dried andconcentrated. The residue was purified by pre-TLC (MeOH/DCM=1/20) togive title product as a yellow solid (40 mg, yield: 29%). ESI-MS (M+H)⁺:464.0.

Preparation of2-(tert-butyl)-N-(4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% ammonia as mobile phase) to give product2-(tert-butyl)-N-(4-(2-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a pale yellow solid (15 mg, yield: 36%). ESI-MS (M+H)⁺: 530.9. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.69 (s, 1H),9.10 (t, J=5.6 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.96-7.94(m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 6.50 (s, 1H),4.50 (d, J=6.0 Hz, 2H), 3.96 (t, J=5.6 Hz, 2H), 3.62 (s, 2H), 2.87 (t,J=5.6 Hz, 2H), 2.56 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.39 (s, 9H), 1.07(t, J=7.2 Hz, 3H).

Example 56:2-(tert-butyl)-N-(2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-57)

Preparation of tert-butyl (3-methylisoxazol-4-yl)carbamate

Diphenyl phosphorazidate (642 mg, 2.34 mmol) and TEA (236 mg, 2.34 mmol)were added to a solution of 3-methylisoxazole-4-carboxylic acid (300 mg,2.34 mmol) in tert-butanol (10 mL) at 50° C. The mixture was stirred at90° C. for 16 h. After concentrated, the residue was purified by silicagel column chromatography (petroleum ether/EtOAc=1:4) to give tert-butyl(3-methylisoxazol-4-yl)carbamate (412 mg, yield: 66%) as a yellow solid.ESI-MS (M+H)⁺: 199.1.

Preparation of 3-methylisoxazol-4-amine

A mixture of tert-butyl (3-methylisoxazol-4-yl)carbamate (150 mg, 0.75mmol) in TFA/DCM (10 mL, 1:1) was stirred at rt for 1 h. Afterconcentrated, the residue was dissolved in DCM (20 mL) and solid K₂CO₃(1 g) was added. The solid was filtered off and the filtrate wasconcentrated to give crude title product (96 mg, yield: 93%), which wasused in nest step without further purification.

Preparation of tert-butyl2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The residue was purified by silica gel chromatography column (petroleumether/EtOAc=1:2) to give tert-butyl2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamateas a yellow solid (234 mg, yield: 59%). ESI-MS (M+H)⁺: 396.1.

Preparation of2-(tert-butyl)-N-(2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-((3-methylisoxazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (54 mg, yield: 59%). ESI-MS: (M+H)⁺:463.0. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.95 (s, 1H), 8.36(d, J=5.6 Hz, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.0 Hz, 1H),7.33 (d, J=8.0 Hz, 1H), 7.19 (d, J=5.6 Hz, 1H), 4.50 (s, 2H), 2.36 (s,3H), 2.26 (s, 3H), 1.35 (s, 9H).

Example 57:2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-58)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 56, starting from1-methyl-1H-1,2,3-triazol-4-amine. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give a yellow solid(35 mg, yield: 25%). ESI-MS (M+H)⁺: 463.2. HPLC: (214 nm: 100%, 254 nm:100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.25 (s, 1H), 9.11-9.08 (m, 1H),8.54 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.98-7.95 (m, 2H),7.42-7.39 (m, 2H), 4.50 (d, J=5.2 Hz, 1H), 4.06 (s, 3H), 2.42 (s, 3H),1.39 (s, 9H).

Example 58:2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-59)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 56, starting from5-methyl-1,3,4-thiadiazol-2-amine. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.05% ammonia as mobile phase) to give product2-(tert-butyl)-N-(2-methyl-4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (100 mg, yield: 54%). ESI-MS (M+H)⁺: 479.9. HPLC: (214nm: 93%, 254 nm: 96%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (t, J=5.6 Hz,1H), 8.63 (d, J=4.4 Hz, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 6.51 (d, J=5.2 Hz, 1H),4.51 (d, J=5.6 Hz, 2H), 2.61 (s, 3H), 2.44 (s, 3H), 1.38 (s, 9H).

Example 59:2-(tert-butyl)-N-(2-methyl-4-(2-(pyridin-2-ylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide.(I-60)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-(pyridin-2-ylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 56, starting from pyridin-2-amine. Theresidue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-(pyridin-2-ylamino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a pale yellow solid (17 mg, yield: 53%). ESI-MS (M+H)⁺: 459.3. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.76 (s, 1H),9.12 (t, J=5.6 Hz, 1H), 8.60 (d, J=4.2 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H),8.34 (s, 1H), 8.29 (dd, J=8.4, 1.2 Hz, 1H), 8.02 (s, 1H), 7.99 (s, 1H),7.83-7.78 (m, 1H), 7.50 (d, J=4.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.00(dd, J=4.2, 1.2 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 2.42 (s, 3H), 1.39 (s,9H).

Example 60:2-(tert-butyl)-N-(4-(2-((5-(dimethylamino)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-61)

Synthesis of2-(tert-butyl)-N-(4-(2-((5-(dimethylamino)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 56. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(4-(2-((5-(dimethylamino)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamideas a pale yellow solid (39 mg, yield: 78%). ESI-MS (M+H)⁺: 502.2. HPLC:(214 nm: 100%, 254 nm: 98%). ¹H NMR (400 MHz, CD₃OD) δ: 8.45 (d, J=5.6Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=9.2 Hz, 1H), 7.99 (s, 1H), 7.91 (s,1H), 7.82 (d, J=2.8 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.37 (dd, J=9.2,3.2 Hz, 1H), 7.33 (d, J=5.6 Hz, 1H), 4.62 (s, 2H), 2.96 (s, 6H), 2.48(s, 3H), 1.47 (s, 9H).

Example 61:2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-62)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 56, starting from5-(4-methylpiperazin-1-yl)pyridin-2-amine. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (18 mg, yield: 17%). ESI-MS: (M+H)⁺:557.0. HPLC: (214nm: 89%, 254 nm: 96%). ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, J=4.8 Hz,1H), 8.29 (d, J=9.2 Hz, 1H), 8.21 (s, 1H), 8.01-7.97 (m, 2H), 7.78 (s,1H), 7.76 (d, J=5.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.05 (d, J=5.2 Hz, 1H),6.41 (br, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.10 (t, J=4.0 Hz, 4H), 2.54 (t,J=4.4 Hz, 4H), 2.36 (s, 3H), 2.29 (s, 3H), 1.37 (s, 9H).

Example 62:2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-63)

Synthesis of tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate was similar to thatof tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate inExample 1, except that 4,6-dichloropyrimidine was substituted for2,4-dichloropyrimidine. Obtained tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (327 mg, yield: 48%)as a white solid. ESI-MS (M+H)⁺: 333.9. ¹H NMR (400 MHz, CDCl₃) δ: 9.02(s, 1H), 7.89 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.40 (d,J=8.4 Hz, 1H), 4.81 (br, 1H), 4.38 (d, J=5.6 Hz, 2H), 2.42 (s, 3H), 1.47(s, 9H).

Synthesis of tert-butyl2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatein Example 1, except that the bicyclic amine shown above was substitutedfor 1-methyl-pyrazol-4-amine, and tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate was substituted fortert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Obtainedtert-butyl2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate(40 mg, yield: 15%) as a yellow solid. ESI-MS (M+H)⁺: 450.1.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of2-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidein Example 1, except that tert-butyl2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzylcarbamatewas substituted for tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.Obtained2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(20 mg, yield: 43%) as a yellow solid. ESI-MS (M+H)⁺: 516.8. HPLC: (214nm: 99.33%, 254 nm: 97.39%). ¹H NMR (400 MHz, CD₃OD) δ: 8.48 (s, 1H),8.13 (s, 1H), 7.68 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.30(d, J=8.0 Hz, 1H), 6.15 (s, 1H), 4.49 (s, 2H), 4.01 (t, J=5.6 Hz, 2H),3.57 (s, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 1.35(s, 9H).

Example 63:2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-64)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 62. Obtained2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(50 mg, yield: 48%) as a white solid. ESI-MS (M+H)⁺: 461.9. HPLC: (214nm: 99.47%, 254 nm: 99.16%). ¹H NMR (400 MHz, CD₃OD) δ: 8.60 (s, 1H),8.24 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.56(s, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.99 (s, 1H), 4.61 (s, 2H), 3.90 (s,3H), 2.46 (s, 3H), 1.47 (s, 9H).

Example 64:2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-65)

Preparation of 1-methyl-1H-imidazol-4-amine

To a solution of 1-methyl-4-nitro-1H-imidazole (500 mg, 3.94 mmol) inMeOH (10 mL) was added Pd/C (50 mg). The mixture was stirred at rt for16 h under hydrogen atmosphere. Then the mixture was filtered and thefiltrate was concentrated in vacuo. The crude product (340 mg. yield:89%) was used in the next step without further purification. ESI-MS(M+H)⁺: 98.1.

Preparation of 6-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrimidin-4-amine

To a solution of 1-methyl-1H-imidazol-4-amine (80 mg, 0.80 mmol) inn-BuOH (4 mL) were added 4,6-dichloropyrimidine (140 mg, 0.96 mmol) andDIPEA (205 mg, 1.60 mmol). The mixture was stirred at 130° C. for 1 hunder microwave. After removal of solution, the residue was purified bysilica gel column chromatography (petroleum ether/EtOAc=2:1) to givecompound 6-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrimidin-4-amine (70 mg,yield: 41%) as a white solid. ESI-MS (M+H)⁺: 210.2. ¹H NMR (400 MHz,CDCl₃) δ: 8.51 (s, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 6.71 (s, 1H), 3.73(s, 3H).

Preparation of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude productwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase)to give2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (40 mg, yield: 26%). ESI-MS (M+H)⁺: 462.1. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.50 (s, 1H), 8.12(s, 1H), 7.68 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.32 (d,J=8.4 Hz, 1H), 7.25 (s, 1H), 7.06 (s, 1H), 4.60 (s, 2H), 3.74 (s, 3H),2.45 (s, 3H), 1.46 (s, 9H).

Example 65:2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-66)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 62, starting from1-methyl-1H-pyrazol-3-amine. The crude product was purified by columnchromatography on silica gel column eluting with petroleum ether/EtOAc(1/4) to give2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(48 mg, yield: 52%) as a yellow solid. ESI-MS (M+1)⁺: 462.2. ¹H NMR (400MHz, CD₃OD) δ: 8.56 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.74 (d, J=7.6Hz, 1H), 7.48-7.37 (m, 3H), 6.37 (s, 1H), 4.57 (s, 2H), 3.82 (s, 3H),2.42 (s, 3H), 1.43 (s, 9H).

Example 66:2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-67)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 62, starting from2-methyl-2H-1,2,3-triazol-4-amine. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give a yellow solid(47 mg, yield: 41%). ESI-MS (M+H)⁺: 463.2. HPLC: (214 nm: 100%, 254 nm:100%). ¹H NMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 9.09 (t, J=5.2 Hz,1H), 8.74 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.82 (d,J=7.6 Hz, 1H), 7.41-7.39 (m, 2H), 4.50 (d, J=5.2 Hz, 2H), 4.10 (s, 3H),2.41 (s, 3H), 1.40 (s, 9H).

Example 67:2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-tetrazol-5-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-68)

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((2-methyl-2H-tetrazol-5-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 62, starting from2-methyl-2H-tetrazol-5-amine. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give a yellow solid (7mg, yield: 11%). ESI-MS (M+H)⁺: 464.2. ¹HNMR (400 MHz, DMSO-d₆) δ: 11.01(s, 1H), 9.10 (t, J=5.6 Hz, 1H), 8.78 (s, 1H), 8.32 (s, 1H), 8.05 (s,1H), 7.89 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.49(d, J=5.2 Hz, 2H), 4.34 (s, 3H), 2.41 (s, 3H), 1.38 (s, 9H).

Example 68:2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-69)

Synthesis of tert-butyl4-(6-aminopyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(6-aminopyrimidin-4-yl)-2-methylbenzylcarbamate was similar to that oftert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Obtainedtert-butyl 4-(6-aminopyrimidin-4-yl)-2-methylbenzylcarbamate (170 mg,yield: 52%) as a white solid. ESI-MS (M+H)⁺: 315.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.66 (s, 1H), 7.81 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.34 (d,J=8.4 Hz, 1H), 6.81 (s, 1H), 4.95 (br, 2H), 4.78 (br, 1H), 4.36 (d,J=5.2 Hz, 2H), 2.39 (s, 3H), 1.47 (s, 9H).

Synthesis of tert-butyl2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.Obtained tert-butyl2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzylcarbamate(30 mg, yield: 21%) as a yellow solid. ESI-MS (M+H)⁺: 490.1.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (28 mg, yield: 39%). ESI-MS (M+H)⁺: 556.9. HPLC: (214nm: 93%, 254 nm: 93%). ¹H NMR (400 MHz, CD₃OD) δ: 8.53 (s, 1H), 8.13 (s,1H), 7.95 (d, J=2.8 Hz, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.69 (d, J=8.0Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 3.2 Hz, 1H), 7.33 (d,J=8.0 Hz, 1H), 4.50 (s, 2H), 3.12 (t, J=4.8 Hz, 4H), 3.55 (t, J=5.2 Hz,4H), 2.36 (s, 3H), 2.27 (s, 3H), 1.36 (s, 9H).

Example 69:2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzyl)thiazole-5-carboxamide(I-70)

Synthesis of tert-butyl 4-(2-aminopyridin-4-yl)-2-methylbenzylcarbamate

To a solution of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(347 mg, 1.0 mmol) in 1,4-dioxane (4 mL) and H₂O (1 mL),4-bromopyridin-2-amine (172 mg, 1.0 mmol), Pd(dppf)Cl₂.DCM (81 mg, 0.1mmol) and K₂CO₃ (276 mg, 2.0 mmol) were added under N₂. The mixture wasstirred at 110° C. for 16 h. After cooling to rt, the mixture wasdiluted with H₂O (20 mL) and extracted with EA (60 mL×2). The organiclayers were collected, concentrated. The residue was purified by columnchromatography (silica, petroleum ether/EtOAc=4:1 to 2:1) to givetert-butyl 4-(2-aminopyridin-4-yl)-2-methylbenzylcarbamate (210 mg,yield: 65%) as a yellow solid. ESI-MS (M+H)⁺: 314.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.09 (d, J=6.0 Hz, 1H), 7.40-7.38 (m, 2H), 7.32 (d, J=8.4 Hz,1H), 6.87 (dd, J=5.6, 1.2 Hz, 1H), 6.70 (s, 1H), 4.76 (br, 1H), 4.62(br, 2H), 4.36 (d, J=5.6 Hz, 2H), 2.38 (s, 3H), 1.47 (s, 9H).

Synthesis of tert-butyl2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.Obtained tert-butyl2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzylcarbamate(75 mg, yield: 51%) as a yellow solid. ESI-MS (M+H)⁺: 489.1.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzyl)thiazole-5-carboxamide

A mixture of tert-butyl2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzylcarbamate(123 mg, 0.25 mmol) in TFA/DCM (4 mL, 1:1) was stirred at rt for 1 h.After concentration, the residue was dissolved in 4 mL DMF and2-(tert-butyl)thiazole-5-carboxylic acid (46 mg, 0.25 mmol), HATU (114mg, 0.30 mmol) and DIPEA (65 mg, 0.50 mmol) were added. After stirringat rt for 16 h, the mixture was diluted with water (20 mL) and extractedwith EtOAc (50 mL×2). The combined organic layer was washed with H₂O (20mL×2), dried (Na₂SO₄), filtered and concentrated. The residue waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) togive2-(tert-butyl)-N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (61 mg, yield: 43%). ESI-MS (M+H)⁺: 556.3. HPLC: (214nm: 99%, 254 nm: 96%). ¹H NMR (400 MHz, CD₃OD) δ: 8.12 (s, 1H), 8.05 (d,J=5.2 Hz, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.43-7.39 (m, 3H), 7.32-7.27(m, 2H), 6.97-6.96 (m, 1H), 4.48 (s, 2H), 3.05 (t, J=4.8 Hz, 4H), 2.51(t, J=4.8 Hz, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 1.34 (s, 9H).

Example 70:2-(tert-butyl)-N-(2-methyl-4-(2-(1-methylpiperidine-4-carboxamido)pyridin-4-yl)benzyl)thiazole-5-carboxamide.(I-71)

Synthesis of N-(4-bromopyridin-2-yl)-1-methylpiperidine-4-carboxamide

To a solution of 1-methylpiperidine-4-carboxylic acid (207 mg, 1.45mmol) and DMF (cat) in DCM (5 mL) was added (COCl)₂(182 mg, 1.45 mmol)at 0° C. The mixture was stirred at rt for 2 h, then the solvent wasremoved. The residue was dissolved in pyridine (5 mL),4-bromopyridin-2-amine (207 mg, 1.2 mmol) was added. The mixture wasstirred at rt for another 16 h. After the solvent was removed, theresidue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobilephase) to give N-(4-bromopyridin-2-yl)-1-methylpiperidine-4-carboxamide(270 mg, yield: 75%) as a white solid. ESI-MS (M+H)⁺: 297.9.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-(1-methylpiperidine-4-carboxamido)pyridin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(2-(1-methylpiperidine-4-carboxamido)pyridin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude productwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase)to give2-(tert-butyl)-N-(2-methyl-4-(2-(1-methylpiperidine-4-carboxamido)pyridin-4-yl)benzyl)thiazole-5-carboxamideas a white solid (40 mg, yield: 26%). ESI-MS (M+H)⁺: 506.3. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (s, 1H), 8.19(d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.44-7.40 (m, 2H), 7.30 (d, J=7.6 Hz,1H), 7.24 (dd, J=5.2, 1.6 Hz, 1H), 4.48 (s, 2H), 2.87-2.82 (m, 2H),2.39-2.35 (m, 1H), 2.32 (s, 3H), 2.17 (s, 3H), 2.02-1.96 (m, 2H),1.82-1.74 (m, 4H), 1.34 (s, 9H).

Example 71: The preparation ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide(I-72)

A mixture of 4-(4-(aminomethyl)-3-methylphenyl)pyrimidin-2-amine (56 mg,0.2 mmol5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylicacid (44 mg, 0.2 mmol), HATU (81 mg, 0.24 mmol) and TEA (34 mg, 2.6mmol) in DMF (3 mL) was stirred at rt for 4 h. After diluted with EtOAc(60 mL), the mixture was washed with water (30 mL) and brine (30 mL).The organic phase was dried and concentrated. The residue was dissolvedin DCM/TFA (4 mL, 1:1) and the mixture was stirred at rt for 1 h. Afterconcentrated, the residue was purified by prep-HPLC (MeOH/H₂O with 0.05%NH₃.H₂O as mobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide(40 mg, yield: 54%) as a white solid. ESI-MS (M+H)⁺: 378.2. ¹H NMR (400MHz, CD₃OD) δ: 8.25 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=8.4 Hz,1H), 7.39 (d, J=8.0 Hz, 1H), 7.12 (d, J=5.6 Hz, 1H), 6.63 (s, 1H), 4.60(s, 2H), 4.47-4.45 (m, 2H), 3.94 (s, 2H), 3.18 (t, J=5.2 Hz, 2H), 2.45(s, 3H), 1.90-1.88 (m, 2H).

Example 72:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxamide(I-73)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxamidewas similar to that of Example 71, starting from6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxylic.The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O asmobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxamide(40 mg, yield: 55%) as a white solid. ESI-MS (M+H)⁺: 395.2. ¹H NMR (400MHz, CD₃OD) δ: 8.26 (d, J=5.6 Hz, 1H), 7.91-7.84 (m, 2H), 7.40 (d, J=8.0Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 4.61 (s, 2H), 3.14-2.98 (m, 8H), 2.46(s, 3H).

Example 73:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide(I-74)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamidewas similar to that of Example 71, starting from7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylicacid. The crude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide(18 mg, yield:51%) as a white solid. ESI-MS (M+H)⁺: 364.1. ¹H NMR (400MHz, CD₃OD) δ: 8.16 (d, J=5.6 Hz, 1H), 7.08 (s, 1H), 7.56 (d, J=8.0 Hz,1H), 7.50 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 4.50(s, 2H), 3.97 (t, J=5.6 Hz, 2H), 3.88 (s, 2H), 3.11 (t, J=5.6 Hz, 2H),2.34 (s, 3H).

Example 74:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(I-75)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamidewas similar to that of Example 71, starting from5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylicacid. The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(36 mg, yield: 42%) as a white solid. ESI-MS (M+H)⁺: 381.1. ¹H NMR (400MHz, CD₃OD) δ: 8.25 (d, J=5.2 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=8.0 Hz,1H), 7.40 (d, J=8.0 Hz, 1H), 7.12 (d, J=6.0 Hz, 1H), 4.33 (s, 2H), 4.09(s, 2H), 3.16 (t, J=5.6 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.46 (s, 3H).

Example 75:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide (I-76)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamidewas similar to that of Example 71, starting from5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid. The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide(28 mg, yield: 45%) as a white solid. ESI-MS (M+H)⁺: 364.2. ¹H NMR (400MHz, CD₃OD) δ: 8.25 (d, J=5.6 Hz, 1H), 7.90-7.84 (m, 2H), 7.39 (d, J=8.0Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 6.54 (s, 1H), 4.61 (s, 2H), 4.19 (t,J=5.2 Hz, 2H), 4.09 (s, 2H), 3.34-3.33 (m, 2H), 2.45 (s, 3H).

Example 76:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(I-77)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamidewas similar to that of Example 71, starting from2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylicacid. The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(38 mg, yield: 47%) as a white solid. ESI-MS (M+H)⁺: 374.2. ¹H NMR (400MHz, DMSO-d₆) δ: 8.86 (t, J=5.6 Hz, 1H), 8.27 (d, J=5.2 Hz, 1H), 7.90(s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.65-7.64 (m, 2H), 7.32 (d, J=8.0 Hz,1H), 7.11-7.09 (m, 2H), 6.64 (s, 2H), 4.48 (d, J=5.2 Hz, 2H), 3.87 (s,2H), 2.95 (t, J=5.6 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.40 (s, 3H).

Example 77:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(I-78)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamidewas similar to that of Example 71, starting from6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylicacid. The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give the compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(15 mg, yield: 23%) as a white solid. ESI-MS (M+H)⁺: 375.1. ¹H NMR (400MHz, CD₃OD) δ: 8.14 (d, J=5.6 Hz, 1H), 7.81-7.78 (m, 2H), 7.73 (d, J=8.0Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.00 (d, J=6.0Hz, 1H), 4.55 (s, 2H), 3.97 (s, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.91 (t,J=6.0 Hz, 2H), 2.33 (s, 3H).

Example 78:(7R,9aR)—N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide(I-79)

Synthesis of(7R,9aR)—N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamidewas similar to that of Example 71, starting from(7R,9aR)-2-(tert-butoxycarbonyl)octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylicacid. The crude was purified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give the compound(7R,9aR)—N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide(43 mg, yield: 52%) as a white solid. ESI-MS (M+H)⁺: 381.3. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.93-7.88 (m, 2H), 7.43 (d, J=8.0Hz, 1H), 7.14 (d, J=5.2 Hz, 1H), 4.50 (ABq, J=80.0, 15.2 Hz, 2H),3.11-2.79 (m, 5H), 2.58-2.57 (m, 1H), 2.47 (s, 3H), 2.41-2.08 (m, 5H),1.79-1.22 (m, 3H).

Example 79:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide(I-80)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1-methyl-1H-pyrazole-4-carboxamidewas similar to that of Example 71, starting from1-methyl-1H-pyrazole-4-carboxylic acid. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to giveN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-1-methyl-1H-pyrazole-4-carboxamideas a white solid (30 mg, yield: 58%). ESI-MS (M+H)⁺: 323.3. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.15 (d, J=5.2 Hz,1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.75 (dd, J=8.0, 1.2 Hz,1H), 7.28 (d, J=8.0 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 4.47 (s, 2H), 3.81(s, 3H), 2.33 (s, 3H).

Example 80:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide(I-81)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydrocyclopenta[c]pyrrole-5-carboxamidewas similar to that of Example 71, starting from2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid.The crude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide(20 mg, yield: 43%) as a white solid. ESI-MS (M+H)⁺: 352.1. ¹HNMR (400MHz, CD₃OD) δ: 8.26 (d, J=5.6 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=8.0 Hz,1H), 7.33 (d, J=8.0 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 4.43 (s, 2H),3.31-3.19 (m, 1H), 2.94-2.85 (m, 2H), 2.74-2.73 m, 3H), 2.52-2.47 (m,1H), 2.41 (s, 3H), 2.24-2.21 (m, 1H), 2.05-1.94 (m, 1H), 1.74-1.71 (m,1H), 1.60-1.55 (m, 1H).

Example 81:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(I-82)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamidewas similar to that of Example 71, starting from6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylicacid. The crude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂Oas mobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(40 mg, yield: 50%) as a white solid. ESI-MS (M+H)⁺: 379.9. ¹H NMR (400MHz, CD₃OD) δ: 8.25 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=9.2 Hz,1H), 7.45 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.12 (d, J=5.6 Hz, 1H), 4.58(s, 2H), 4.01 (s, 2H), 3.08 (t, J=5.6 Hz, 2H), 2.71 (t, J=6.0 Hz, 2H),2.44 (s, 3H).

Example 82:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-83)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(trifluoromethyl)thiazole-5-carboxamidewas similar to that of Example 71, starting from2-(trifluoromethyl)thiazole-5-carboxylic acid. The crude was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givecompoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(trifluoromethyl)thiazole-5-carboxamide(15 mg, yield: 33%) as a white solid. ESI-MS (M+H)⁺: 394.0. ¹H NMR (400MHz, CD₃OD) δ: 8.41 (s, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.82 (s, 1H), 7.78(d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 4.54(s, 2H), 2.36 (s, 3H).

Example 83:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-84)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide wassimilar to that of Example 71, starting from thiazole-5-carboxylic acid.The crude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide (51mg, yield: 53%) as a white solid. ESI-MS (M+H)⁺: 326.0. ¹H NMR (400 MHz,DMSO-d₆) δ: 9.24 (s, 1H), 9.21 (t, J=5.6 Hz, 1H), 8.56 (s, 1H), 8.28 (d,J=5.2 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz,1H), 7.10 (d, J=5.2 Hz, 1H), 6.67 (s, 2H), 4.50 (d, J=5.2 Hz, 2H), 2.39(s, 3H).

Example 84:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-cyclopropylthiazole-5-carboxamide(I-85)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-cyclopropylthiazole-5-carboxamidewas similar to that of Example 71, starting from2-cyclopropylthiazole-5-carboxylic acid. A white solid (62 mg, yield:53%) was obtained. ESI-MS (M+H)⁺: 366.0. HPLC: (214 nm: 100%, 254 nm:94%). ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=5.6 Hz, 1H), 8.14 (s, 1H),7.92 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.12 (d,J=5.6 Hz, 1H), 4.59 (s, 2H), 2.45-2.41 (m, 4H), 1.25-1.21 (m, 2H),1.11-1.09 (m, 2H).

Example 85:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-isopropylthiazole-5-carboxamide(I-86)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-isopropylthiazole-5-carboxamidewas similar to that of Example 71, starting from2-isopropylthiazole-5-carboxylic acid. ObtainedN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-isopropylthiazole-5-carboxamide(70 mg, yield: 63%) as a light yellow solid. ESI-MS (M+H)⁺: 368.0. HPLC:(214 nm: 100%, 254 nm: 99.60%). ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d,J=5.2 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.40(d, J=8.0 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 4.61 (s, 2H), 3.38-3.32 (m,1H), 2.45 (s, 3H), 1.42 (d, J=6.8 Hz, 6H).

Example 86:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(1-methoxyethyl)thiazole-5-carboxamide(I-87)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(1-methoxyethyl)thiazole-5-carboxamidewas similar to that of Example 71, starting from2-(1-methoxyethyl)thiazole-5-carboxylic acid. ObtainedN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(1-methoxyethyl)thiazole-5-carboxamide(75 mg, yield: 65%) as a light yellow solid. ESI-MS (M+H)⁺: 384.0. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (s, 1H),8.26 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.41 (d,J=8.0 Hz, 1H), 7.13 (d, J=5.6 Hz, 1H), 4.67 (q, J=6.4 Hz, 1H), 4.62 (s,2H), 3.44 (s, 3H), 2.46 (s, 3H), 1.54 (d, J=6.0 Hz, 3H).

Example 87:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tetrahydrofuran-2-yl)thiazole-5-carboxamide(I-88)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tetrahydrofuran-2-yl)thiazole-5-carboxamidewas similar to that of Example 71, starting from2-(tetrahydrofuran-2-yl)thiazole-5-carboxylic acid. A white solid (56mg, yield: 44%) was obtained. ESI-MS (M+H)⁺: 396.1. HPLC: (214 nm: 100%,254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.28 (s, 1H), 8.25 (d, J=6.4Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H),7.12 (d, J=6.4 Hz, 1H), 5.21-5.17 (m, 1H), 4.60 (s, 2H), 4.12-4.08 (m,1H), 3.98-3.93 (m, 1H), 2.49-2.44 (m, 4H), 2.12-1.99 (m, 3H).

Example 88:2-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)thiazole-5-carboxamide(I-89)

Synthesis of (E)-5-(3-bromophenyl)pent-4-enoic acid

To a solution of (3-carboxypropyl)triphenylphosphonium bromide (12.87 g,30 mmol, 1.0 equiv) in dry DMSO (50 mL) was added NaH (3 g, 75 mmol, 2.5equiv) by portions at 0° C. The reaction was stirred at room temperaturefor 30 min before 3-bromobenzaldehyde (5.5 g, 30 mmol, 1.0 equiv) wasdropwise added. The mixture was stirred at room temperature for another2 h and then poured into water (200 mL) and extracted with EA (100 mL).The aqueous solution was acidified with concentrated HCl and extractedwith EA (200 mL×3). The combined organic layer was washed with brine(100 mL×3). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column (petroleum ether/EtOAc=2:1) to give(E)-5-(3-bromophenyl)pent-4-enoic acid (4.4 g, yield: 58%) as a yellowoil. ESI-MS (M+1)⁺: 254.9. ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (s, 1H), 7.33(d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H),6.39-6.35 (m, 1H), 6.23-6.19 (m, 1H), 2.55-2.53 (m, 4H).

Synthesis of 5-(3-bromophenyl)pentanoic acid

To a solution of (E)-5-(3-bromophenyl)pent-4-enoic acid (2.4 g, 9.4mmol, 1.0 equiv) in ethanol (20 mL) was added PtO₂ (200 mg, 10%). Themixture was stirred for 1 h under hydrogen atmosphere. The catalyst wasfiltered out and the resulting filtrate was concentrated to give targetcompound 5-(3-bromophenyl)pentanoic acid (2.1 g, yield: 87%) as a yellowsolid, which was used to next step without further purification. ESI-MS(M+1)⁺: 256.9. ¹H NMR (400 MHz, CD₃OD) δ: 7.24 (s, 1H), 7.21-7.18 (m,1H), 7.06-7.03 (m, 2H), 2.50 (t, J=6.8 Hz, 2H), 2.20 (t, J=6.8 Hz, 2H),1.53-1.51 (m, 4H).

Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

A mixture of 5-(3-bromophenyl)pentanoic acid (2.1 g, 8.2 mmol, 1.0equiv) in PPA (5 ml) was stirred at 130° C. for 1 h. After cooling down,the mixture was basified to pH=7˜8 with NaOH (1 N). The mixture wasextracted with EtOAc (200 mL×2). The combined organic layers wasconcentrated and purified by prep-HPLC (Gradient: 5% B increase to 95%B, A: 0.5% NH₃ in water, B: CH₃CN) to give2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.1 g, yield: 56%)as a colorless oil. ESI-MS (M+H)⁺: 239.0. ¹H NMR (400 MHz, CDCl₃) δ:7.59 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (s, 1H), 2.89(t, J=6.8 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 1.90-1.79 (m, 4H).

Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol

To a solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(600 mg, 2.5 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH₄ (144 mg,3.8 mmol, 1.5 equiv) and then stirred at room temperature for 1 h. Afterevaporation of the solvent, the residue was purified by silica gelcolumn (EtOAc/hexane=1:5) to give2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600 mg, yield: 99%)as a white solid. ESI-MS (M+H-17)⁺: 222.9. ¹H NMR (400 MHz, CDCl₃) δ:7.34-7.30 (m, 2H), 7.24 (s, 1H), 4.88-4.86 (m, 1H), 2.88-8.82 (m, 1H),2.70-2.63 (m, 1H), 2.08-2.00 (m, 2H), 1.81-1.72 (m, 4H).

Synthesis of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene

A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600mg, 2.5 mmol, 1.0 equiv) in toluene (10 mL) was cooled in an ice bathunder N₂ and treated with DPPA (2.06 g, 7.5 mmol, 3.0 equiv) in oneportion followed by DBU (1.14 g, 7.5 mmol, 3.0 equiv). The reactiontemperature was kept at 0° C. for 1 h and then was warmed to roomtemperature for 12 h. The mixture was diluted with EtOAc (100 mL),washed with 2N HCl (2×50 mL), brine and the organic layer was dried overNa₂SO₄, filtered then concentrated. The crude product was purified bysilica gel column (eluted with PE) to give5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (350 mg, yield:45%) as a yellow oil. ESI-MS (M+H—N₃)⁺: 223.0. ¹H NMR (400 MHz, CDCl₃)δ: 7.31-7.29 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H),2.99-2.92 (m, 1H), 2.70-2.64 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.59 (m,5H).

Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine

To a mixture of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene(375 mg, 1.4 mmol, 1.0 equiv) in THF (5 mL) and H₂O (0.5 mL) was addedPPh₃ (741 mg, 2.8 mmol, 2.0 equiv). The mixture was stirred at roomtemperature for 12 h. The mixture was acidified to pH=1 with HCl (1 N)and extracted with EA (100 mL). The separated aqueous layer was basifiedto pH=10 with NaOH (1 N). The resulting precipitate was collected anddried to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (360mg, yield: 100%) as a white solid. ESI-MS (M+H-17)⁺: 222.9.

Synthesis of tert-butyl(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

To a mixture of tert-butyl(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (360 mg,1.5 mmol, 1.0 equiv) in DCM (5 mL) and TEA (303 mg, 3.0 mmol, 2.0 equiv)was added Boc₂O (394 mg, 1.8 mmol, 1.2 equiv). The mixture was stirredat room temperature for 2 h. After diluted with EtOAc (100 mL), themixture was washed with water (100 mL×2). The organic layer wasconcentrated and purified by silica gel column (PE:EA=30:1) to givetert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(310 mg, yield: 61%) as a white solid. ESI-MS (M-55): 284.0. ¹H NMR (400MHz, CDCl₃) δ: 7.29-7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 4.92-4.82 (m,2H), 2.84-2.75 (m, 2H), 1.88-1.83 (m, 5H), 1.44 (s, 9H).

Synthesis of tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

Synthesis of tert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture wasconcentrated and purified by silica gel column (PE:EA=4:1) to givetert-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(200 mg, yield: 66%) as a white solid. ESI-MS (M+H)⁺: 374.1.

Synthesis of tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

Synthesis of tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The mixture was concentrated and purified by silica gel column(DCM:MeOH=30:1) to give tert-butyl(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(80 mg, yield: 34%) as a yellow solid. ESI-MS (M+H)⁺: 435.2.

Synthesis of2-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)thiazole-5-carboxamide(32 mg, yield: 69%) as a yellow solid. ESI-MS (M+1)⁺: 502.2. ¹H NMR (400MHz, CD₃OD) δ: 8.39 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 7.95 (s, 1H),7.92-7.91 (m, 2H), 7.64 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.18 (d, J=5.2Hz, 1H), 5.38-5.35 (m, 1H), 3.87 (s, 3H), 3.10-2.95 (m, 2H), 2.10-1.77(m, 5H), 1.48 (s, 9H), 1.43-1.38 (m, 1H).

Example 89:2-(tert-butyl)-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)thiazole-5-carboxamide(I-90)

Synthesis of tert-butyl(5-(2-chloropyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Synthesis of tert-butyl(5-(2-chloropyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate wassimilar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture wasconcentrated and purified by silica gel column (petroleumether/EtOAc=4:1) to give tert-butyl(5-(2-chloropyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (790 mg,yield: 49%) as a yellow solid. ESI-MS (M+H)⁺: 346.0. ¹H NMR (400 MHz,CDCl₃) δ: 8.62 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=7.6 Hz, 1H),7.62 (d, J=5.2 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.27-5.21 (m, 1H),4.81-4.79 (m, 1H), 3.07-3.00 (m, 1H), 2.95-2.87 (m, 1H), 2.66-2.63 (m,1H), 1.90-1.85 (m, 1H), 1.50 (s, 9H).

Synthesis of tert-butyl(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Synthesis of tert-butyl(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The mixture was purified by silica gel column (petroleumether/EtOAc=1:1) to give tert-butyl(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(80 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 406.9. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 7.88-7.87 (m, 3H), 7.54 (s, 1H),7.42 (d, J=7.6 Hz, 1H), 7.06-7.05 (m, 2H), 5.27-5.21 (m, 1H), 4.81-4.78(m, 1H), 3.07-2.88 (m, 2H), 2.65-2.59 (m, 1H), 1.95-1.80 (m, 1H), 1.50(s, 9H).

Synthesis of2-(tert-butyl)-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)thiazole-5-carboxamide(48 mg, yield: 43%) as a yellow solid. ESI-MS (M+H)⁺: 474.0. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.89(d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.45 (d, J=8.0 Hz, 1H),7.07-7.06 (m, 2H), 6.21 (d, J=8.0 Hz, 1H), 5.75-5.68 (m, 1H), 3.90 (s,3H), 3.13-2.95 (m, 2H), 2.79-2.70 (m, 1H), 2.00-1.95 (m, 1H), 1.45 (s,9H).

Example 90:2-(tert-butyl)-N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-91)

Synthesis of2-(tert-butyl)-N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamidewas similar to that of Example 89. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give2-(tert-butyl)-N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamideas yellow solid (90 mg, yield: 76%). ESI-MS (M+H)⁺: 488.2. ¹H NMR (400MHz, DMSO-d₆) δ: 9.53 (s, 1H), 9.01 (d, J=8.4 Hz, 1H), 8.46 (d, J=5.2Hz, 1H), 8.33 (s, 1H), 7.93-7.92 (m, 3H), 7.53 (s, 1H), 7.36 (d, J=8.4Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), 5.24-5.22 (m, 1H), 3.82 (s, 3H),2.89-2.88 (m, 2H), 2.02-2.00 (m, 2H), 1.83-1.81 (m, 2H), 1.39 (s, 9H).

Example 91:2-(tert-butyl)-N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-92)

Synthesis of tert-butyl(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate

Synthesis of tert-butyl(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Obtained tert-butyl(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(170 mg, yield: 47%) as a white solid. ESI-MS (M+H)⁺: 421.1. ¹H NMR (400MHz, CDCl₃) δ: 8.71 (s, 1H), 7.71 (s, 1H), 7.68-7.65 (m, 2H), 7.50 (s,1H), 7.42 (d, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.45 (s, 1H), 4.91-4.87 (m,1H), 4.80-4.77 (m, 1H), 3.94 (s, 3H), 2.85-2.80 (m, 2H), 2.12-2.07 (m,1H), 1.86-1.77 (m, 3H), 1.48 (s, 9H).

Synthesis of2-(tert-butyl)-N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamidewas similar to that of Example 1. Obtained2-(tert-butyl)-N-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(55 mg, yield: 50%) as a white solid. ESI-MS (M+H)⁺: 488.1. ¹H NMR (400MHz, CD₃OD) δ: 8.43 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.58 (s, 1H),7.57 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.82 (s,1H), 5.18-5.16 (m, 1H), 3.71 (s, 3H), 2.80-2.77 (m, 2H), 2.00-1.77 (m,4H), 1.35 (s, 9H).

Example 92:N-(6-(6-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamide(I-93)

Synthesis ofN-(6-(6-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 89. ObtainedN-(6-(6-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamide(32 mg, yield: 26%) as a white solid. ESI-MS (M+H)⁺: 474.1. ¹H NMR (400MHz, CD₃OD) δ: 8.84 (s, 1H), 8.23 (s, 1H), 8.06-8.04 (m, 2H), 7.66-7.63(m, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 5.34-5.32 (m, 1H),3.00-2.90 (m, 2H), 2.17-1.93 (m, 4H), 1.46 (s, 9H).

Example 93: Synthesis ofN-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-94)

Synthesis ofN-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 89, starting from6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid. ObtainedN-(6-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(45 mg, yield: 43%) as a white solid. ESI-MS (M+H)⁺: 486.8. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.56 (br, 1H),8.76 (d, J=8.8 Hz, 1H), 8.63 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.57(d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.29 (d, J=8.4 Hz, 1H),7.04 (s, 1H), 5.22-5.17 (m, 1H), 4.58 (s, 2H), 3.87 (t, J=5.6 Hz, 2H),3.83 (s, 3H), 2.86-2.82 (m, 4H), 2.03-1.98 (m, 2H), 1.86-1.79 (m, 2H).

Example 94:N-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-95)

Synthesis ofN-(6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 89 starting from6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid. The residue waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) togive title product as a yellow solid (23 mg, yield: 24%). ESI-MS (M+H)⁺:487.2. HPLC: (214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ:8.44 (d, J=4.8 Hz, 1H), 7.98-7.93 (m, 3H), 7.60 (s, 1H), 7.46 (s, 1H),7.38 (d, J=8.0 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 5.30-5.26 (m, 1H), 4.62(s, 2H), 3.94-3.91 (m, 2H), 3.86 (s, 3H), 2.94-2.86 (m, 4H), 2.10-1.84(m, 4H), 1.28-1.27 (m, 2H).

Example 95:2-(tert-butyl)-N-(6-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-96)

Synthesis of2-(tert-butyl)-N-(6-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamidewas similar to that of Example 89. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give2-(tert-butyl)-N-(6-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamideas a white solid (10 mg, yield: 18%). ESI-MS (M+H)⁺: 582.9. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 9.50 (s, 1H), 9.00(d, J=6.8 Hz, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.33 (s, 1H), 8.17 (d, J=7.2Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.97-7.95 (m, 2H), 7.48 (dd, J=7.6, 2.4Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 5.24-5.21 (m,1H), 3.12 (t, J=3.2 Hz, 4H), 2.89 (s, 2H), 2.46 (t, J=4.0 Hz, 4H), 2.22(s, 3H), 2.02-1.97 (m, 2H), 1.86-1.83 (m, 2H), 1.37 (s, 9H).

Example 96:2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)thiazole-5-carboxamide(I-97)

Synthesis of 7-bromochroman-4-ol

To a solution of 7-bromochroman-4-one (1.63 g, 7.2 mmol, 1.0 equiv) inMeOH (10 mL) was added NaBH₄ (545 mg, 14.4 mmol, 2.0 equiv) and thenstirred at room temperature for 30 minutes. After evaporation of thesolvent, the residue was purified by silica gel column(EtOAc/hexane=1:2) to give 7-bromochroman-4-ol (1.61 g, yield: 98%) as awhite solid. ESI-MS (M+H-18)⁺: 211.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.17(d, J=8.0 Hz, 1H), 7.05-7.01 (m, 2H), 4.76-4.73 (m, 1H), 4.27-4.24 (m,2H) 2.14-1.99 (m, 2H).

Synthesis of 4-azido-7-bromochroman

A solution of 7-bromochroman-4-ol (200 mg, 0.88 mmol, 1.0 equiv) intoluene (5 mL) was cooled in an ice bath under N₂ and treated with DPPA(532 mg, 1.93 mmol, 2.2 equiv) in one portion followed by DBU (293 mg,1.93 mmol, 2.2 equiv). The reaction temperature was kept at 0° C. for 1h and then was warmed to room temperature for 16 h. The mixture wasdiluted with EtOAc (50 mL), washed with 2N HCl (2×30 mL), brine and theorganic layer was dried over Na₂SO₄, filtered then concentrated. Thecrude product was purified by silica gel column (eluted with PE).4-azido-7-bromochroman (188 mg, yield: 90%) was obtained as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ: 7.07-7.06 (m, 3H), 4.56 (t, J=3.6 Hz,1H), 4.30-4.17 (m, 2H), 2.19-1.99 (m, 2H).

Synthesis of 7-bromochroman-4-amine

A solution of 4-azido-7-bromochroman (2.2 g, 8.7 mmol, 1.0 equiv) in THF(50 mL) and H₂O (10 mL) was treated with PPh₃ (4.5 g, 17 mmol, 2.0equiv). The mixture was stirred at room temperature for 16 h. Afterconcentrated to dryness, the residue was diluted with 1N HCl (100 mL),extracted with EA (100 mL). The aqueous was basified to pH=10 with 2NNaOH, extracted with EtOAc (50 mL×2). The combined organic extracts weredried over Na₂SO₄, filtered then concentrated. 7-bromochroman-4-amine(1.4 g, yield: 71%) was obtained as a colorless oil. ESI-MS (M+H-17)⁺:210.9.

Synthesis of tert-butyl (7-bromochroman-4-yl)carbamate

To a solution of 7-bromochroman-4-amine (1.4 g, 6.16 mmol, 1.0 equiv) indichloromethane (30 mL) were added Et₃N (933 mg, 9.24 mmol, 1.5 equiv)and Boc₂O (1.5 g, 6.8 mmol, 1.1 equiv). The reaction solution wasstirred at room temperature for 2 h. The mixture was concentrated andpurified by silica gel column (petroleum ether/EtOAc=30:1). tert-butyl(7-bromochroman-4-yl)carbamate (1.5 g, yield: 74%) was obtained as awhite solid. ESI-MS (M+H-56)⁺: 272.0. ¹H NMR (400 MHz, CDCl₃) δ:7.14-7.12 (m, 1H), 7.03-6.98 (m, 2H), 4.78-4.77 (m, 1H), 4.27-4.11 (m,2H) 2.19-1.99 (m, 2H), 1.48 (s, 9H).

Synthesis of tert-butyl(7-(2-chloropyrimidin-4-yl)chroman-4-yl)carbamate

The synthesis of tert-butyl(7-(2-chloropyrimidin-4-yl)chroman-4-yl)carbamate was similar to that oftert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Theresidue was purified by silica gel column column (petroleumether/EtOAc=4:1) to give tert-butyl(7-(2-chloropyrimidin-4-yl)chroman-4-yl)carbamate (500 mg, yield: 70%)as a white solid. ESI-MS (M+H)⁺: 362.0. ¹H NMR (400 MHz, CDCl₃) δ:8.62(d, J=5.2 Hz, 1H), 7.78 (d, J=5.2 Hz, 1H), 7.65-7.63 (m, 1H), 7.56 (s,1H), 7.42 (d, J=7.6 Hz, 1H), 4.86 (t, J=5.2 Hz, 1H), 4.31-4.27 (m, 2H),2.24-2.05 (m, 2H), 1.21 (s, 9H).

Synthesis of tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-ylcarbamate

To a mixture of tert-butyl(7-(2-chloropyrimidin-4-yl)chroman-4-yl)carbamate (180 mg, 0.5 mmol) and1-methyl-pyrazol-4-amine (97 mg, 1.0 mmol, 2.0 equiv) in dioxane (5 mL),Cs₂CO₃ (489 mg, 1.5 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol) and S-Phos (41mg, 0.1 mmol) were added under N₂. The mixture was stirred at 120° C.for 12 h. After diluted with EtOAc (150 mL), the mixture was washed withbrine and the organic layer was dried over Na₂SO₄, filtered thenconcentrated. The residue was purified by silica gel column (petroleumether/EtOAc=1:1) to give tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)carbamate(120 mg, yield: 57%) as a yellow solid. ESI-MS (M+H)⁺: 423.1. ¹H NMR(400 MHz, DMSO-d₆) δ: 9.46 (s, 1H), 8.45-8.44 (m, 1H), 7.89 (s, 1H),7.65 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.43 (d, J=8.8 Hz,1H), 7.32-7.30 (m, 1H), 7.23-7.21 (m, 1H), 4.83-4.74 (m, 1H), 4.31-4.21(m, 2H), 3.82 (s, 3H), 2.11-1.87 (m, 2H), 1.44 (s, 9H).

Synthesis of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)chroman-4-yl)thiazole-5-carboxamide(48 mg, yield: 43%) as a yellow solid. ESI-MS (M+H)⁺: 490.0. ¹H NMR (400MHz, DMSO-d₆) δ: 9.49 (s, 1H), 9.06 (d, J=8.0 Hz, 1H), 8.45 (d, J=5.2Hz, 1H), 8.32-8.31 (m, 1H), 7.88 (s, 1H), 7.67 (d, J=8.0 Hz, 1H),7.58-7.57 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H),5.28-5.26 (m, 1H), 4.33-4.31 (m, 2H), 3.82 (s, 3H), 2.19-1.99 (m, 2H),1.39 (s, 9H).

Example 97:2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)thiazole-5-carboxamide(I-98)

Synthesis of 4-bromo-2-(hydroxymethyl)benzoic acid

Lithium hydroxide (3.45 g, 70.42 mmol, 3.0 equiv) was added at roomtemperature over several minutes to a solution of 5-bromophthalide (5.0g, 23.47 mmol, 1.0 equiv) in a 2:1:1 solution of THF/MeOH/H₂O (80 mL)and the reaction mixture was stirred at room temperature for 16 h. Afterremoval of the solvent, the residue was diluted with water (100 mL),adjusted to pH=3 with HCl (2 N) and extracted with EtOAc (100 mL×3). Theorganic layers were collected, dried (Na₂SO₄), filtered, andconcentrated via rotary evaporator to give title product (3.47 g, yield:94%) as a white solid, which was used in the next step without furtherpurification. ESI-MS (M+H)⁺: 231.1. ¹H NMR (400 MHz, CD₃OD) δ: 7.88-7.86(m, 2H), 7.45 (dd, J=8.4, 2.0 Hz, 1H), 4.90 (s, 2H).

Synthesis of 4-bromo-2-((carboxymethoxy)methyl)benzoic acid

Sodium hydride (3.46 g, 86.56 mmol, 4.0 equiv) was added in smallportions over the course of 0.5 h at room temperature to a mixture of4-bromo-2-(hydroxymethyl)benzoic acid (5.0 g, 21.64 mmol, 1.0 equiv) andbromoacetic acid (2.99 g, 21.64 mmol) in THF (60 mL), then sodium iodide(324.6 mg, 2.164 mmol, 0.1 equiv) was added. The reaction mixture washeated at reflux for 16 h. The reaction mixture was cooled to roomtemperature and poured into water (150 mL) and then extracted withdiethyl ether (100 mL×3). The aqueous phase was acidified with 10%hydrochloric acid to pH=3-4 and extracted with ethyl acetate (200 mL×3).The combined ethyl acetate phases were washed with water (150 mL) andbrine, dried (sodium sulfate), filtered, and concentrated to yield4-bromo-2-((carboxymethoxy)methyl)benzoic acid as a white solid (4.37 g,yield: 70%), which was used for next step without further purification.¹H NMR (400 MHz, CD₃OD) δ: 7.93-7.87 (m, 2H), 7.55-7.52 (m, 1H), 4.98(s, 2H), 4.23 (s, 2H).

Synthesis of 7-bromoisochroman-4-one

A solution of 4-bromo-2-((carboxymethoxy)methyl)benzoic acid (5.2 g,18.06 mmol, 1.0 equiv) in acetic anhydride (100 mL) containing potassiumacetate (7.61 g, 77.64 mmol, 4.3 equiv) was heated at reflux for 2 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure and the residue partitioned between ethyl acetate(200 mL) and water (100 mL). The phases were separated and the aqueousphase was extracted with ethyl acetate (100 mL×3). The combined ethylacetate phases were then washed with brine, dried (sodium sulfate),filtered and concentrated. The residue was dissolved in EtOH (50 mL),NaOH (2.89 g, 72.24 mmol, 4.0 eq) was added. The reaction mixture wasstirred at rt for 2 h. After concentration, the residue was portionedbetween ethyl acetate (200 mL) and water (100 mL), washed with saturatedbrine, dried (sodium sulfate), filtered and concentrated. The residuewas purified by column chromatography (silica, petroleumether/EtOAc=1:1) to give 7-bromoisochroman-4-one (725 mg, yield: 18%) asa slight yellow solid. ESI-MS (M+H)⁺: 227.0. ¹H NMR (400 MHz, CDCl₃) δ:7.90 (d, J=8.4 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.42 (s, 1H), 4.86(s, 2H), 4.36 (s, 2H).

Synthesis of 7-bromoisochroman-4-ol

Synthesis of 7-bromoisochroman-4-ol was similar to that of7-bromochroman-4-ol. The crude (1.3 g, yield: 89%) was used directly inthe next step without further purification. ESI-MS (M+H)⁺: 229.0. ¹H NMR(400 MHz, CDCl₃) δ: 7.42-7.40 (m, 1H), 7.34-7.32 (m, 1H), 7.17 (s, 1H),4.66 (ABq, J=20.4, 15.2 Hz, 2H), 4.51-4.50 (m, 1H), 4.12-4.10 (m, 1H),3.84-3.80 (m, 1H).

Synthesis of 4-azido-7-bromoisochroman

Synthesis of 4-azido-7-bromoisochroman was similar to that of4-azido-7-bromochroman. The residue was purified by columnchromatography (silica, petroleum ether/EtOAc=50:1) to give4-azido-7-bromoisochroman (568 mg, yield: 39%) as a white solid. ESI-MS(M+H-28)⁺: 226.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.44 (m, 1H),7.28-7.24 (m, 2H), 4.77 (ABq, J=20.4, 15.6 Hz, 2H), 4.22-4.16 (m, 2H),3.96-3.92 (m, 1H).

Synthesis of 7-bromoisochroman-4-amine

To a solution of 4-azido-7-bromoisochroman (207 mg, 0.82 mmol, 1.0 eq)in THF (5 mL), 1N LiAlH₄ (0.82 mL, 0.82 mmol, 1.0 equiv) was added at 0°C. Then the mixture was refluxed for 1 h. After cooling down to rt,Na₂SO₄.10H₂O was added and the mixture was stirred for another 0.5 h.The solid was filtered off and the filtrate was concentrated to givetitle product (153 mg, yield: 82%), which was used directly for nextstep without further purification. ESI-MS (M+H)⁺: 228.0.

Synthesis of tert-butyl (7-bromoisochroman-4-yl)carbamate

Synthesis of tert-butyl (7-bromoisochroman-4-yl)carbamate was similar tothat of tert-butyl (7-bromochroman-4-yl)carbamate. The crude waspurified by prep-HPLC (MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) togive compound tert-butyl (7-bromoisochroman-4-yl)carbamate (332 mg,yield: 55%) as a white solid. ESI-MS (M+H-56)⁺: 272.05. ¹H NMR (400 MHz,CDCl₃) δ: 7.38-7.30 (m, 2H), 7.15 (s, 1H), 5.11-5.09 (m, 1H), 4.75-4.63(m, 3H), 4.04-4.00 (m, 1H), 3.86-3.82 (m, 1H), 1.45 (s, 9H).

Synthesis of tert-butyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-yl)carbamate

Synthesis of tert-butyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-yl)carbamatewas similar to that of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate.The residue was purified by column chromatography (silica, petroleumether/EtOAc=10:1) to give tert-butyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-yl)carbamate(310 mg, yield: 81%) as a white solid. ESI-MS (M+H-56)⁺: 320.2.

Preparation of tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)carbamate

Synthesis of tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)carbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The residue was purified by column chromatography (silica, petroleumether/EtOAc=1:2) to give title compound as a yellow solid (272 mg,yield: 79%). ESI-MS (M+H-56)⁺: 367.2.

Preparation of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)isochroman-4-yl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give a yellow solid(105 mg, yield: 61%). ESI-MS (M+H)⁺: 490.2. HPLC: (214 nm: 100%, 254 nm:100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.52 (s, 1H), 9.07 (d, J=8.4 Hz,1H), 8.48 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J=8.0 Hz, 1H),7.92-7.91 (m, 2H), 7.54 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.26 (d, J=5.2Hz, 1H), 5.25-5.21 (m, 1H), 4.92-4.83 (m, 2H), 4.09-4.01 (m, 1H),3.85-3.80 (m, 4H), 1.39 (s, 9H).

Example 98:2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamide(I-99)

Preparation of methyl 3-((3-bromophenyl)amino)propanoate

A mixture of 3-bromoaniline (10.00 g, 58.14 mmol) and methyl acrylate(5.30 mL, 58.14 mmol) in acetic acid (0.4 mL) was refluxed for 16 h.Then the solution was concentrated, and the residue was purified bysilica gel column chromatography (petroleum ether/EtOAc=1/10 to 1/6) togive product methyl 3-((3-bromophenyl)amino)propanoate (11.92 g, yield:80%) as red liquid. ESI-MS (M+H)⁺: 257.8

Preparation of methyl3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoate

To a solution of methyl 3-((3-bromophenyl)amino)propanoate (11.90 g,46.30 mmol) in pyridine (10 mL) was added p-tosyl chloride (10.58 g,55.56 mmol) portionwise at room temperature. The mixture was stirred foranother 2 h. The mixture was concentrated and the residue was dilutedwith EtOAc (20 mL). The organic phase was washed with 1N HCl (60 mL) andbrine (60 mL×2). After drying over Na₂SO₄, filtered and concentrated,the residue was purified by silica gel column chromatography (petroleumether/EtOAc=1/10 to 1/4) to give product methyl3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoate (15.30 g,yield: 80%) as brown sticky oil. ESI-MS (M+H)⁺: 411.9.

Preparation of 3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoicacid

A solution of methyl3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoate (15.23 g,37.06 mmol) in concentrated HCl (21.80 mL), water (68.6 mL) and1,4-dioxane (192.6 mL) was heated at reflux for 5 h. Then the solutionwas concentrated to half volume (˜130 mL), neutralized with saturatedNaHCO₃solution to pH=8-9 and extracted with EtOAc (80 mL×3). Thecombined organic phase was back-extracted with water (80 mL). Thecombined aqueous phase was acidified by conc. HCl solution (pH=3),extracted with EtOAc (80 mL×3). The organic phase was combined and driedover Na₂SO₄, filtered and concentrated to dryness to give3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoic acid (7.00 g,yield: 48%) as brown oil. ESI-MS (M+H)⁺: 397.9.

Preparation of 7-bromo-2,3-dihydroquinolin-4(1H)-one

A solution of 3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoicacid (5.00 g, 12.59 mmol), SOCl₂ (4.60 mL, 62.97 mmol) and one drop ofDMF in DCM (20 mL) was refluxed for 2 h. Then the solution wasconcentrated to dryness to give carboxylic chloride which was used fornext step. A mixture of AlCl₃ (3.40 g, 25.18 mmol) in DCM (20 mL) wascooled at 5° C., and then a solution of carboxylic chloride preparedabove in DCM (10 mL) was added dropwise over 30 min. After addition, thesolution was stirred at room temperature for 3 h. Then the solution wasquenched with ice water, neutralized with NaOH solution, and extractedwith EtOAc (50 mL×3). The combined organic phase was dried (Na₂SO₄) andconcentrated. The residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=1/4) to give product7-bromo-2,3-dihydroquinolin-4(1H)-one as a yellow solid (1.86 g, yield:54%). ESI-MS (M+H)⁺: 226.0

Preparation of 7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-one

Synthesis of 7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-one was similarto that of methyl3-(N-(3-bromophenyl)-4-methylphenylsulfonamido)propanoate. The residuewas purified by silica gel column chromatography (petroleumether/EtOAc=1/6) to give product7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-one as a yellow solid (2.57 g,yield: 85%). ESI-MS (M+H)⁺: 380.0. ¹H NMR (400 MHz, CD₃OD) δ: 8.02 (d,J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.47 (dd,J=8.4, 1.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 4.25 (t, J=6.4 Hz, 2H), 2.42(s, 3H), 2.38 (t, J=6.4 Hz, 2H).

Preparation of(E)-N-(7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)-2-methylpropane-2-sulfinamide

A solution of 7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-one (700 mg,1.84 mmol), t-butylsulfinamide (245 mg, 2.02 mmol) and titanium ethoxide(890 mg, 3.68 mmol) in dry THF (10 mL) was heated at reflux for 16 h.Then the mixture was diluted with EA (150 mL) and washed with brine (60mL), water (60 mL). The organic phase was dried (Na₂SO₄) andconcentrated to give crude product(E)-N-(7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)-2-methylpropane-2-sulfinamideas a white solid (740 mg, yield: 83%) which was used directly in thenext step. ESI-MS (M+H)⁺: 482.9.

Preparation of 7-bromo-1-tosyl-1,2,3,4-tetrahydroquinolin-4-amine

To a solution of(E)-N-(7-bromo-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)-2-methylpropane-2-sulfinamide(740 mg, 1.53 mmol) in methanol (7 mL) was added sodium borohydride (117mg, 3.07 mmol) portionwise at 0° C. Then the mixture was stirred at roomtemperature for 2 h. The organic solvent was removed under reducedpressure, and the residue was dissolved in EtOAc (7 mL) and treated withconc. HCl (3 mL). The mixture was stirred at room temperature for 16 h.Then the mixture was adjusted to pH=8 with solid sodium bicarbonate andextracted with EtOAc (10 mL). The organic phase was washed with water(40 mL), dried (Na₂SO₄) and concentrated to give crude product7-bromo-1-tosyl-1,2,3,4-tetrahydroquinolin-4-amine as a white solid (400mg crude) which was used directly in the next step. ESI-MS (M+H)⁺: 381.0

Preparation of tert-butyl(7-bromo-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Synthesis of tert-butyl(7-bromo-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate was similarto that of tert-butyl (7-bromochroman-4-yl)carbamate. The residue waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/6)to give product tert-butyl(7-bromo-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate as a whitefoam (438 mg, yield: 60% for two steps). ESI-MS (M+H)⁺: 480.9. ¹H NMR(400 MHz, CD₃OD) δ: 7.96 (d, J=1.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.35(d, J=8.4 Hz, 2H), 7.28 (dd, J=8.4, 1.6 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H),4.35-4.31 (m, 1H), 4.03-3.97 (m, 1H), 3.79-3.72 (m, 1H), 2.40 (s, 3H),1.78-1.61 (m, 2H), 1.40 (s, 9H).

Preparation of tert-butyl(7-(2-chloropyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Synthesis of tert-butyl(7-(2-chloropyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The residue waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/6to 1/4) to give product tert-butyl(7-(2-chloropyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamateas a white solid (208 mg, yield: 61%). ESI-MS (M+H)⁺: 515.1.

Preparation of tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Synthesis of tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The residue waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/2to 2/1) to give product tert-butyl(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamateas a green solid (92 mg, yield: 40%). ESI-MS (M+H)⁺: 576.2.

Preparation of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified silica gelcolumn chromatography (petroleum ether/EtOAc=2/1) to give product2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamideas a yellow solid (70 mg, yield: 73%). ESI-MS (M+H)⁺: 643.2.

Synthesis of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamide

A solution of2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamide(60 mg, 0.09 mmol) in conc. HCl solution (1.5 mL) was heated at 50° C.for 3 h. Then the mixture was concentrated and the residue was dissolvedin EtOAc (50 mL). The organic phase was washed with saturated Na₂CO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified byprep-HPLC (MeCN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give product2-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)thiazole-5-carboxamideas a pale yellow solid (12 mg, yield: 27%). ESI-MS (M+H)⁺: 489.0. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.35 (d, J=5.6Hz, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.35 (d, J=1.6 Hz,1H), 7.32 (dd, J=8.0, 1.6 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (d,J=5.6 Hz, 1H), 5.30 (t, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.40 (t, J=5.6 Hz,2H), 2.14-2.09 (m, 2H), 1.46 (s, 9H).

Example 99:2-(tert-butyl)-N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)thiazole-5-carboxamide(I-100)

Synthesis of tert-butyl((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)carbamate

To a solution of tert-butyl((5-bromo-3-methylpyridin-2-yl)methyl)carbamate (150 mg, 0.5 mmmol) indioxane (2 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (140 mg,0.55 mmol, 1.1 equiv), Pd(dppf)Cl₂.DCM (20 mg, 0.025 mmol, 0.05 equiv)and KOAc (147 mg, 1.5 mmol, 3 equiv). The mixture was heated to 110° C.for 1 h under N₂. After cooled to rt,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (100 mg, 0.5mmol, 1 equiv), Pd(dppf)Cl₂.DCM (20 mg, 0.025 mmol, 0.05 equiv) andK₂CO₃ (138 mg, 1 mmol, 2 equiv) were added. The mixture was heated to100° C. for another 2 h. After diluted with EA (150 mL), the mixture waswashed with water (50 mL×2). The organic phase was concentrated and thecrude was purified through silica gel column chromatography (petroleumether/EtOAc=2/1) to give tert-butyl((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)carbamateas a yellow solid (145 mg, yield: 70%). ESI-MS (M+H)⁺: 396.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.99 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.07 (s, 1H),7.88 (s, 1H), 7.55 (s, 1H), 7.45 (br, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.24(s, 1H), 4.48 (d, J=4.0 Hz, 2H), 3.91 (s, 3H), 2.37 (s, 3H), 1.49 (s,9H).

Synthesis of2-(tert-butyl)-N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude was purified throughprep-TLC (MeOH/DCM=1/25) to give2-(tert-butyl)-N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)thiazole-5-carboxamideas a yellow solid (50 mg, yield: 65%). ESI-MS (M+H)⁺: 463.2. HPLC: (214nm: 98.74%, 254 nm: 98.43%). ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (s, 1H),8.48 (d, J=5.2 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.00 (br, 1H), 7.85(s, 1H), 7.58 (s, 1H), 7.14 (s, 1H), 7.09 (d, J=5.2 Hz, 1H), 4.72 (d,J=4.0 Hz, 2H), 3.93 (s, 3H), 2.42 (s, 3H), 1.48 (s, 9H).

Example 100:N-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-101)

Synthesis ofN-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 99. Purified through prep-TLC(MeOH/DCM=1/20) to giveN-((3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(40 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 462.1. HPLC: (214nm: 94.50%, 254 nm: 95.27%). ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (s, 1H),8.47 (d, J=4.8 Hz, 1H), 8.12 (s, 1H), 7.96 (br, 1H), 7.83 (s, 1H), 7.61(s, 1H), 7.33 (s, 1H), 7.09 (d, J=5.2 Hz, 1H), 6.99 (s, 1H), 4.73 (s,2H), 4.72 (d, J=4.0 Hz, 2H), 4.00 (t, J=5.2 Hz, 2H), 3.93 (s, 3H), 2.92(t, J=5.2 Hz, 2H), 2.43 (s, 3H).

Example 101:2-(tert-butyl)-N-((6-methyl-2′-((1-methyl-1H-pyrazol-4-yl)amino)-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide(I-102)

Synthesis ofN-((6-bromo-2-methylpyridin-3-yl)methyl)-2-(tert-butyl)thiazole-5-carboxamide

Synthesis ofN-((6-bromo-2-methylpyridin-3-yl)methyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 1. The residue was purified by silica gelcolumn (petroleum ether/EtOAc=2:1) to giveN-((6-bromo-2-methylpyridin-3-yl)methyl)-2-(tert-butyl)thiazole-5-carboxamide(140 mg, yield: 38%) as a yellow solid. ESI-MS (M+1)⁺: 368.0. ¹H NMR(400 MHz, CD₃OD) δ: 8.21 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 4.52 (s, 2H), 2.55 (s, 3H), 1.45 (s, 9H).

Synthesis of2-(tert-butyl)-N-((2′-chloro-6-methyl-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-((2′-chloro-6-methyl-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture waspurified by silica gel column (petroleum ether/EtOAc=1:1) to give2-(tert-butyl)-N-((2′-chloro-6-methyl-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide(80 mg, yield: 52%) as a yellow solid. ESI-MS (M+H)⁺: 400.9. ¹H NMR (400MHz, CDCl₃) δ: 8.43 (d, J=4.8 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.78(dd, J=5.2, 0.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H),6.36 (t, J=5.6 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 2.67 (s, 3H), 1.45 (s,9H).

Synthesis of2-(tert-butyl)-N-((6-methyl-2′-((1-methyl-1H-pyrazol-4-yl)amino)-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-((6-methyl-2′-((1-methyl-1H-pyrazol-4-yl)amino)-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamidewas similar to that of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine.The mixture was purified by prep-HPLC (Gradient: 5% B increase to 95% B,A: 0.5% NH₃ in water, B: CH₃CN) to give2-(tert-butyl)-N-((6-methyl-2′-((1-methyl-1H-pyrazol-4-yl)amino)-[2,4′-bipyridin]-5-yl)methyl)thiazole-5-carboxamide(20 mg, yield: 22%) as a brown solid. ESI-MS (M+H)⁺: 462.1. ¹H NMR (400MHz, CDCl₃) δ: 8.20 (d, J=6.4 Hz, 1H), 8.10 (s, 1H), 7.67 (s, 1H), 7.69(d, J=0.8 Hz, 1H), 7.45-7.43 (m, 2H), 7.16 (dd, J=5.2, 0.8 Hz, 1H), 7.13(s, 1H), 6.78 (t, J=5.6 Hz, 1H), 6.38 (s, 1H), 4.60 (d, J=5.6 Hz, 2H),3.87 (s, 3H), 2.59 (s, 3H), 1.45 (s, 9H).

Example 102:2-(tert-butyl)-N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)thiazole-5-carboxamide(I-103)

Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)guanidine

To a solution of 1-methyl-1H-pyrazol-4-amine (500 mg, 5 mmol, 1.0 equiv)in dioxane (10 mL) was added NCNH₂ (273 g, 6.5 mmol, 1.3 equiv) andconc. HCl (1 mL). The reaction was stirred at 100° C. for 12 h. Thesolvent was removed under reduced pressure. The residue wasrecrystallized from the co-solvent of MeOH and Et₂O.1-(1-methyl-1H-pyrazol-4-yl)guanidine (600 mg, yield: 55%) was obtainedas a yellow solid. ESI-MS (M+H)⁺: 140.1. ¹H NMR (400 MHz, CD₃OD) δ: 7.78(s, 1H), 7.48 (s, 1H), 3.91 (s, 3H).

Synthesis of tert-butyl ((6-bromo-2-methylpyridin-3-yl)methyl)carbamate

To a mixture of 1-(1-methyl-1H-pyrazol-4-yl)guanidine (709 mg, 3 mmol,1.0 equiv) in DCM (10 mL) and TEA (909 mg, 9.0 mmol, 3.0 equiv) wasadded Boc₂O (981 mg, 4.5 mmol, 1.5 equiv). The mixture was stirred atroom temperature for 12 h. After concentrated, the residue was purifiedby silica gel column (petroleum ether/EtOAc=8:1) to give tert-butyl((6-bromo-2-methylpyridin-3-yl)methyl)carbamate (728 mg, yield: 82%) asa white solid. ESI-MS (M+H)⁺: 301.2. ¹H NMR (400 MHz, CDCl₃) δ: 7.41 (d,J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.26 (d, J=5.6 Hz, 2H), 2.52 (s,3H), 1.45 (s, 9H).

Synthesis of tert-butyl ((6-acetyl-2-methylpyridin-3-yl)methyl)carbamate

To a mixture of tert-butyl((6-bromo-2-methylpyridin-3-yl)methyl)carbamate (1.49 g, 5 mmol, 1.0equiv) and tributyl(1-ethoxyvinyl)stannane (2.7 g, 7.5 mmol, 2.0 equiv)in toluene (20 ml), Pd(PPh₃)₄ (288 mg, 0.25 mmol, 0.05 equiv) was addedquickly under N₂. The mixture was stirred at 120° C. for 2 h. Aftercooling down, the mixture was concentrated and purified by silica gelcolumn (petroleum ether/EtOAc=4:1) to give the intermediate, which wasdissolved in 5 mL THF and followed by addition of a solution of HCl (0.6N, 1 mL, 6 mmol, 1.2 equiv). After stirred at rt for 5 m and basified topH=8 with sat. sodium bicarbonate, the mixture was extracted with EA(100 mL), washed with water (50 mL), brine (50 mL) and the organic layerwas dried over Na₂SO₄, filtered then concentrated to give tert-butyl((6-acetyl-2-methylpyridin-3-yl)methyl)carbamate (550 mg, yield: 42%) asa yellow solid. ESI-MS (M+H)⁺: 265.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.85(d, J=7.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 4.93 (br, 1H), 4.36 (d, J=5.6Hz, 2H), 2.70 (s, 3H), 2.59 (s, 3H), 1.46 (s, 9H).

Synthesis of (E)-tert-butyl((6-(3-(dimethylamino)acryloyl)-2-methylpyridin-3-yl)methyl)carbamate

A solution of tert-butyl((6-acetyl-2-methylpyridin-3-yl)methyl)carbamate (550 mg, 2.1 mmol, 1.0equiv) in DMF-DMA (5 mL) was stirred at 110° C. for 12 h. Afterevaporation of the solvent, the residue was purified by silica gelcolumn (DCM:MeOH=20:1) to give (E)-tert-butyl((6-(3-(dimethylamino)acryloyl)-2-methylpyridin-3-yl)methyl)carbamate(600 mg, yield: 90%) as a yellow oil. ESI-MS (M+H)⁺: 320.2. ¹H NMR (400MHz, CDCl₃) δ:7.94 (d, J=8.0 Hz, 1H), 7.90-7.86 (m, 1H), 7.62 (d, J=8.0Hz, 1H), 6.47 (d, J=12.0 Hz, 1H), 4.85 (br, 1H), 4.36 (d, J=5.2 Hz, 2H),3.16 (s, 3H), 2.99 (s, 3H), 2.59 (s, 3H), 1.46 (s, 9H).

Synthesis of tert-butyl((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)carbamate

A solution of (E)-tert-butyl((6-(3-(dimethylamino)acryloyl)-2-methylpyridin-3-yl)methyl)carbamate(300 mg, 0.95 mmol, 1.0 equiv) in EtOH (10 mL) was treated with1-(1-methyl-1H-pyrazol-4-yl)guanidine (400 mg, 1.89 mmol, 2.0 equiv) andK₂CO₃ (393 g, 2.85 mmol, 3.0 equiv). The reaction was stirred at 80° C.for 12 h. After cooling down, the crude product was purified byprep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B:CH₃CN) to give tert-butyl((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)carbamate(120 mg, yield: 32%) as a yellow solid. ESI-MS (M+H)⁺: 396.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.50 (d, J=5.2 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.86(s, 1H), 7.72-7.68 (m, 2H), 7.57 (s, 1H), 6.91 (s, 1H), 4.85 (br, 1H),4.38 (d, J=5.2 Hz, 2H), 3.92 (s, 3H), 2.62 (s, 3H), 1.47 (s, 9H).

Synthesis of2-(tert-butyl)-N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)thiazole-5-carboxamide(35 mg, yield: 54%) as a yellow solid. ESI-MS (M+H)⁺:463.1. ¹H NMR (400MHz, CD₃OD) δ: 8.49 (d, J=5.2 Hz, 1H), 8.25-8.23 (m, 2H), 7.99 (s, 1H),7.83 (d, J=8.0 Hz, 1H), 7.66 (d, J=5.2 Hz, 1H), 7.62 (s, 1H), 4.64 (s,2H), 3.89 (s, 3H), 2.67 (s, 3H), 1.47 (s, 9H).

Example 103:N-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-104)

Synthesis ofN-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 102 starting from6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid. The mixture wasstirred at room temperature for 12 h. The mixture was purified byprep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B:CH₃CN) to giveN-((2-methyl-6-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)methyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(20 mg, yield: 29%) as a yellow solid. ESI-MS (M+H)⁺:462.1. ¹H NMR (400MHz, CDCl₃) δ: 8.51 (d, J=5.2 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.85 (s,1H), 7.72-7.70 (m, 2H), 7.55 (s, 1H), 7.22 (s, 1H), 6.95 (s, 1H), 6.21(t, J=5.6 Hz, 1H), 4.67-4.66 (m, 4H), 3.98 (t, J=5.6 Hz, 2H), 3.91 (s,3H), 2.90 (t, J=5.6 Hz, 2H), 2.66 (s, 3H).

Example 104:N-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-105)

Preparation of tert-butyl(1-(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)carbamate

Synthesis of tert-butyl(1-(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)carbamate wassimilar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified by silica gel column chromatography (petroleum ether/EtOAc=1/4)to give product tert-butyl(1-(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)carbamate as greenoil (460 mg, yield: 60%). ESI-MS (M+H)⁺: 347.9.

Preparation of tert-butyl(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)carbamate

Synthesis of tert-butyl(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)carbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude was purified by silica gel column chromatography (petroleumether/EtOAc=4/1 to 1/2) to give product tert-butyl(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)carbamateas green oil (165 mg, yield: 30%). ESI-MS (M+H)⁺: 408.9.

Preparation ofN-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide

Synthesis ofN-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 1. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.01% ammonia as mobile phase) to give productN-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamideas a white solid (77 mg, yield: 81%). ESI-MS (M+H)⁺: 475.0. HPLC: (214nm: 93%, 254 nm: 94%). ¹H NMR (400 MHz, CD₃OD) δ: 8.34 (d, J=4.8 Hz,1H), 7.94-7.89 (m, 3H), 7.63 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.43 (s,1H), 7.13 (d, J=5.2 Hz, 1H), 5.40-5.37 (m, 1H), 4.64 (s, 2H), 3.93 (t,J=5.6 Hz, 2H), 3.86 (s, 3H), 2.84 (t, J=5.6 Hz, 2H), 2.49 (s, 3H), 1.53(d, J=6.8 Hz, 3H).

Example 105:2-(tert-butyl)-N-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide(I-106)

Synthesis of2-(tert-butyl)-N-(1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamidewas similar to that of Example 1. ESI-MS (M+H)⁺: 476.0. ¹H NMR (400 MHz,CD₃OD) δ: 8.32 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 7.93-7.88 (m, 3H), 7.62(s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 5.39-5.37 (m,1H), 3.85 (s, 3H), 2.48 (s, 3H), 1.53 (d, J=7.2 Hz, 3H), 1.42 (s, 9H).

Example 106:N-(1-(4-(2-aminopyrimidin-4-yl)-2-methylphenyl)ethyl)-2-(trifluoromethyl)thiazole-5-carboxamide(I-107)

Synthesis ofN-(1-(4-(2-aminopyrimidin-4-yl)-2-methylphenyl)ethyl)-2-(trifluoromethyl)thiazole-5-carboxamidewas similar to that of Example 1. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(1-(4-(2-aminopyrimidin-4-yl)-2-methylphenyl)ethyl)-2-(trifluoromethyl)thiazole-5-carboxamideas a white solid (20 mg, yield: 57%). ESI-MS (M+H)⁺: 408.0. HPLC: (214nm: 96%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.46 (s, 1H), 8.15(d, J=5.2 Hz, 1H), 7.79-7.78 (m, 2H), 7.47 (d, J=8.8 Hz, 1H), 7.47 (d,J=5.2 Hz, 1H), 5.36-5.31 (m, 1H), 2.41 (s, 3H), 1.48 (d, J=7.2 Hz, 3H).

Example 107:2-(tert-butyl)-N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide(I-108)

Preparation of2-(tert-butyl)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-methyl-4-(2-((1-methyl-M-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified by silica gel column chromatography (EtOAc/petroleum ether=1/2to 2/1) to give product2-(tert-butyl)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamideas a yellow solid (64 mg, yield: 50%). ESI-MS (M+H)⁺: 606.2.

Preparation of2-(tert-butyl)-N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-M-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide

A mixture of2-(tert-butyl)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamide(64 mg, 0.10 mmol) in HCl (3M solution in methanol) was stirred at roomtemperature for 1 h. Then the solution was concentrated and the residuewas purified by prep-HPLC (CH₃CN/water as mobile phase) to give product2-(tert-butyl)-N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)thiazole-5-carboxamideas a yellow solid (27 mg, yield: 55%). ESI-MS (M+H)⁺: 492.0. HPLC: (214nm: 97%, 254 nm: 97%). ¹H NMR (400 MHz, CD₃OD) δ: 8.37 (d, J=5.6 Hz,1H), 8.33 (s, 1H), 7.94-7.93 (m, 3H), 7.64 (s, 1H), 7.51 (d, J=8.0 Hz,1H), 7.16 (d, J=5.6 Hz, 1H), 5.47-5.44 (m, 1H), 3.88 (s, 3H), 3.86-3.83(m, 2H), 2.57 (s, 3H), 1.45 (s, 9H).

Example 108:N-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-109)

Synthesis ofN-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 107, except6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude was purified byprep-HPLC (CH₃CN/water as mobile phase) to give productN-(2-hydroxy-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamideas a yellow solid (40 mg, yield: 51%). ESI-MS (M+H)⁺: 491.0. HPLC: (214nm: 98%, 254 nm: 98%). ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J=5.2 Hz,1H), 7.96-7.93 (m, 3H), 7.64 (s, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.49 (s,1H), 7.19 (d, J=5.2 Hz, 1H), 5.44 (t, J=6.8 Hz, 1H), 4.69 (s, 2H), 3.96(t, J=5.6 Hz, 2H), 3.89 (s, 3H), 3.84 (d, J=6.8 Hz, 2H), 2.88 (t, J=5.6Hz, 2H), 2.58 (s, 3H).

Example 109:N-(4-(2-amino-5-fluoropyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-110)

Synthesis ofN-(4-(2-amino-5-fluoropyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate, starting from4-chloro-5-fluoropyrimidin-2-amine. Purified through silica gel columnchromatography with (MeOH/DCM=1/20) to giveN-(4-(2-amino-5-fluoropyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(45 mg, yield: 59%) as a white solid. ESI-MS (M+H)⁺: 400.1. HPLC: (214nm: 98.20%, 254 nm: 97.80%). ¹H NMR (400 MHz, CD₃OD) δ: 8.24 (s, 1H),8.23 (d, J=4.0 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.42 (d,J=8.0 Hz, 1H), 4.61 (s, 2H), 2.45 (s, 3H), 1.46 (s, 9H).

Example 110:2-(tert-butyl)-N-(4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-111)

Synthesis of tert-butyl4-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylbenzylcarbamate

To a mixture of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(220 mg, 0.63 mmol, 1.0 equiv) and 2,4-dichloro-5-fluoropyrimidine (209mg, 1.26 mmol, 2.0 equiv) in dioxane (5 ml) and H₂O (0.5 mL), NaHCO₃(159mg, 1.89 mmol, 3.0 equiv), Pd(dppf)Cl₂.DCM (46 mg, 0.06 mmol, 0.1 equiv)were added quickly under N₂. The mixture was stirred at 80° C. for 6 h.After cooling down and diluted with water (20 mL), the mixture wasextracted with EtOAc (80 mL×2). The organic phase was concentrated andpurified by silica gel column (petroleum ether/EtOAc=4:1) to givetert-butyl 4-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylbenzylcarbamate(180 mg, yield: 71%) as a white solid. ESI-MS (M+H)⁺: 352.0. ¹H NMR (400MHz, CDCl₃) δ: 8.49 (d, J=3.2 Hz, 1H), 7.95-7.93 (m, 2H), 7.40 (d, J=8.4Hz, 1H), 4.81 (br, 1H), 4.38 (d, J=4.8 Hz, 2H), 2.41 (s, 3H), 1.47 (s,9H).

Synthesis of tert-butyl4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate,starting from 1-methyl-1H-pyrazol-4-amine. The mixture was purified bysilica gel column (DCM:MeOH=40:1) to give tert-butyl4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate(200 mg, yield: 94%) as a yellow solid. ESI-MS (M+H)⁺: 413.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.29 (d, J=3.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.82 (s,1H), 7.52 (s, 1H), 7.39-7.37 (m, 1H), 6.88 (s, 1H), 4.83-4.76 (m, 1H),4.38 (d, J=4.8 Hz, 2H), 3.90 (s, 3H), 2.41 (s, 3H), 1.47 (s, 9H).

Synthesis of2-(tert-butyl)-N-(4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of Example 1. The mixture was purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive2-(tert-butyl)-N-(4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(38 mg, yield: 45%) as a yellow solid. ESI-MS (M+H)⁺: 480.0. ¹H NMR (400MHz, CDCl₃) δ: 8.30 (d, J=2.8 Hz, 1H), 8.06 (s, 1H), 7.90-7.87 (m, 2H),7.81 (s, 1H), 7.48 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.18(t, J=5.6 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 3.89 (s, 3H), 2.45 (s, 3H),1.45 (s, 9H).

Example 111:2-(tert-butyl)-N-(2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-112)

Synthesis of tert-butyl4-(2-chloro-5-methylpyrimidin-4-yl)-2-methylbenzylcarbamate

Synthesis of tert-butyl4-(2-chloro-5-methylpyrimidin-4-yl)-2-methylbenzylcarbamate was similarto that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate, starting from2,4-dichloro-5-methylpyrimidine. Purified through silica gel columnchromatography with (petroleum ether/EtOAc=6/1) to give tert-butyl4-(2-chloro-5-methylpyrimidin-4-yl)-2-methylbenzylcarbamate (200 mg,yield: 44%) as a white solid. ESI-MS (M+H)⁺: 348.2.

Synthesis of tert-butyl2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate,starting from 1-methyl-1H-pyrazol-4-amine. Purified through silica gelcolumn chromatography with (petroleum ether/EtOAc=1/1) to givetert-butyl2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate(230 mg, yield: 78%) as a yellow solid. ESI-MS (M+H)⁺: 409.1. ¹H NMR(400 MHz, DMSO-d₆) δ: 9.30 (s, 1H), 8.31 (s, 1H), 7.83 (s, 1H),7.47-7.45 (m, 3H), 7.38 (t, J=6.0 Hz, 1H), 7.30 (d, J=7.2 Hz, 1H), 4.18(d, J=5.6 Hz, 2H), 3.77 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.41 (s,9H).

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. Purified through silica gel columnchromatography with (petroleum ether/EtOAc=2/1) to give2-(tert-butyl)-N-(2-methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(60 mg, yield: 52%) as a yellow solid. ESI-MS (M+H)⁺: 476.1. HPLC: (214nm: 97.05%, 254 nm: 97.87%). ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (s, 1H),8.24 (s, 1H), 7.90 (s, 1H), 7.57 (s, 1H), 7.49-7.46 (m, 2H), 7.43 (d,J=7.6 Hz, 1H), 4.63 (s, 2H), 3.84 (s, 3H), 2.46 (s, 3H), 2.22 (s, 3H),1.46 (s, 9H).

Example 112:N-((5-(2-aminopyrimidin-4-yl)-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-113)

Synthesis ofN-((5-bromo-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

To a solution of (5-bromo-3-fluoropyridin-2-yl)methanamine (480 mg, 2mmol) in DMF (10 mL) were added4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (364 mg, 2 mmol),HBTU (909 mg, 2.4 mmol) and TEA (606 mg, 6 mmol). The mixture wasstirred at rt for 16 h. After diluted with EtOAc (180 mL), the mixturewas washed with H₂O (60 mL×2) and brine (60 mL), dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=2:1) to giveN-((5-bromo-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (496 mg, yield: 77%). ESI-MS (M+H)⁺: 369.0. ¹H NMR (400MHz, DMSO-d₆) δ: 8.85 (t, J=5.6 Hz, 1H), 8.54 (s, 1H), 8.16 (dd, J=9.6,1.6 Hz, 1H), 7.47 (s, 1H), 4.52 (d, J=4.8 Hz, 2H), 2.71 (t, J=5.6 Hz,2H), 2.55 (t, J=5.6 Hz, 2H), 1.76-1.70 (m, 4H).

Synthesis of(5-fluoro-6-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)pyridin-3-yl)boronicacid

To a solution ofN₄(5-bromo-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(147 mg, 0.4 mmol) in dry dioxane (5 mL,) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (116 mg,0.48 mmol), KOAc (78 mg, 0.8 mmol) and Pd(dppf)Cl₂DCM (33 mg, 0.04 mmol)under nitrogen. The mixture was stirred at 90° C. for 2 h. After coolingdown to rt, the mixture was filtered through Celite pad and the filtratewas purified by prep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) togive compound(5-fluoro-6-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)pyridin-3-yl)boronicacid (115 mg, yield: 86%) as light yellow solid ESI-MS (M+H)⁺: 335.1. ¹HNMR (400 MHz, DMSO-d₆) δ: 8.83 (t, J=5.6 Hz, 1H), 8.64 (s, 1H), 7.84 (d,J=10.4 Hz, 1H), 7.60 (s, 1H), 4.57 (d, J=5.2 Hz, 2H), 2.71 (t, J=5.6 Hz,2H), 2.55 (t, J=5.6 Hz, 2H), 1.76-1.72 (m, 4H).

Synthesis ofN-((5-(2-aminopyrimidin-4-yl)-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

Synthesis ofN-((5-(2-aminopyrimidin-4-yl)-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude productwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase)to give compoundN-((5-(2-aminopyrimidin-4-yl)-3-fluoropyridin-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(23 mg, yield: 12%) as light yellow solid. ESI-MS (M+H)⁺: 384.2. HPLC:(214 nm: 95.06%, 254 nm: 99.27%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s,1H), 8.89 (t, J=4.8 Hz, 1H), 8.37 (d, J=4.8 Hz, 1H), 8.26-8.23 (m, 1H),7.50 (s, 1H), 7.25 (d, J=4.8 Hz, 1H), 6.84 (s, 2H), 4.62 (d, J=5.2 Hz,2H), 2.72 (t, J=5.6 Hz, 2H), 2.57 (t, J=5.6 Hz, 2H), 1.78-1.72 (m, 4H).

Example 113:2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyridazin-4-yl)benzyl)thiazole-5-carboxamide(I-114)

Synthesis of2-(tert-butyl)-N-(4-(6-hydroxypyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(6-hydroxypyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate, starting from5-chloropyridazin-3-ol. The residue was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₃.H₂O as mobile phase) to give compound2-(tert-butyl)-N-(4-(6-hydroxypyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(200 mg, yield: 87%) as a white solid. ESI-MS (M+H)⁺: 383.2.

Synthesis of2-(tert-butyl)-N-(4-(6-chloropyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

A mixture of2-(tert-butyl)-N-(4-(6-chloropyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(200 mg, 0.52 mmol) in POCl₃ (10 mL) was stirred at 80° C. for 1 h. Themixture was evaporated and the residue was purified by pre-TLC(petroleum ether/EtOAc=1:1) to give2-(tert-butyl)-N-(4-(6-chloropyridazin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(90 mg, yield: 43%) as a white solid. ESI-MS (M+H)⁺: 401.1.

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyridazin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyridazin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate,starting from 1-methyl-1H-pyrazol-4-amine. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givecompound2-(tert-butyl)-N-(2-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyridazin-4-yl)benzyl)thiazole-5-carboxamide(7 mg, yield: 7%) as a yellow solid. ESI-MS (M+H)⁺: 462.2. ¹HNMR (400MHz, CD₃OD) δ:8.72 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 7.96 (s, 1H),7.47-7.45 (m, 3H), 7.34 (d, J=7.6 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 4.51(s, 2H), 3.79 (s, 3H), 2.37 (s, 3H), 1.36 (s, 9H).

Example 114:N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-115)

Synthesis of tert-butyl 4-bromo-2-(trifluoromethyl)benzylcarbamate

To a solution of 4-bromo-2-(trifluoromethyl)benzonitrile (2.5 g, 10mmol) in THF (10 mL) in an ice/water bath was added BH₃/THF (1M, 30 mL,30 mmol, 3 equiv) slowly under nitrogen. After addition, the mixture washeated to 80° C. for 16 h. The mixture was cooled to rt and quenchedwith methanol, acidized with a solution of HCl (conc.) in EA. The formedprecipitate was collected through filtering to give a white solid. Thesolid was dissolved in DCM (20 mL) followed by addition of Boc₂O (2.38g, 11 mmol) and TEA (3.03 g, 30 mmol, 3 equiv). The mixture was stirredat rt for 2 h. The solvent was diluted with DCM (80 mL), washed withbrine (20 mL×2). The organic layer was dried, concentrated. The crudewas purified through silica gel column chromatography (EtOAc/petroleumether=1/10) to give tert-butyl4-bromo-2-(trifluoromethyl)benzylcarbamate as a white solid (1.76 g,yield: 50%). ESI-MS (M+H-56)⁺: 298.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.76(s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 4.91 (br, 1H),4.44 (d, J=6.4 Hz, 2H), 1.45 (s, 9H).

Synthesis of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzylcarbamate

Synthesis of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate.Purified through silica gel column chromatography with (EtOAc/petroleumether=1/10) to give tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzylcarbamate(268 mg, yield: 45%) as a while solid. ESI-MS (M+Na)⁺: 424.1.

Synthesis of tert-butyl4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamate

Synthesis of tert-butyl4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamate wassimilar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Purified throughsilica gel column chromatography with (EtOAc/petroleum ether=1/5) togive tert-butyl4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamate (175 mg,yield: 70%) as a while solid. ESI-MS (M+H)⁺: 388.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.70 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.25 (d, J=8.4 Hz, 1H),7.75 (d, J=8.0 Hz, 1H), 7.67 (d, J=5.2 Hz, 1H), 5.00 (br, 1H), 4.57 (d,J=6.0 Hz, 2H), 1.47 (s, 9H).

Synthesis of tert-butyl4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamate

Synthesis of tert-butyl4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude was purified through silica gel column chromatography(EtOAc/petroleum ether=3/2) to give tert-butyl4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzylcarbamateas a yellow solid (105 mg, yield: 60%). ESI-MS (M+H)⁺: 449.1. ¹H NMR(400 MHz, DMSO-d₆) δ: 9.58 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.47 (s,1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.59(t, J=6.0 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J=5.2 Hz, 1H), 4.39 (d, J=5.2Hz, 2H), 3.82 (s, 3H), 1.46 (s, 9H).

Synthesis ofN-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide

Synthesis ofN-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 1. Purified through prep-TLC(MeOH/DCM=1/25) to giveN-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(45 mg, yield: 75%) as a yellow solid. ESI-MS (M+H)⁺: 515.0. HPLC: (214nm: 100%, 254 nm: 99.25%). ¹H NMR (400 MHz, CDCl₃) δ: 8.47 (d, J=5.2 Hz,1H), 8.41 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.18 (s, 1H), 7.09 (d, J=5.2 Hz, 1H), 7.00 (s,1H), 6.31 (t, J=6.0 Hz, 1H), 4.84 (d, J=5.6 Hz, 2H), 4.67 (s, 2H), 3.97(t, J=5.6 Hz, 2H), 3.92 (s, 3H), 2.89 (t, J=5.6 Hz, 2H).

Example 115:2-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)thiazole-5-carboxamide.(I-116)

Synthesis of2-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)thiazole-5-carboxamidewas similar to that of Example 1. Purified through prep-TLC(MeOH/DCM=1/20) to give2-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)thiazole-5-carboxamide(30 mg, yield: 57%) as a yellow solid. ESI-MS (M+H)⁺: 516.2. HPLC: (214nm: 100%, 254 nm: 98.40%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.59 (s, 1H),9.30 (t, J=6.0 Hz, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.50 (s, 1H), 8.39 (d,J=8.0 Hz, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55(s, 1H), 7.38 (d, J=5.2 Hz, 1H), 4.70 (d, J=5.6 Hz, 2H), 3.81 (s, 3H),1.40 (s, 9H).

Example 116:N-(2-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-117)

Synthesis ofN-(2-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 115, starting from(4-bromo-2-fluorophenyl)methanamine. The resulting product is purifiedby column chromatography on silica gel (PE/EA=2:1-1:2) to giveN-(2-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(22 mg, yield: 24%) as a white solid. ESI-MS (M+H)⁺: 465.2. ¹H NMR (400MHz, CDCl₃) δ: 8.44 (d, J=5.2 Hz, 1H), 7.85 (s, 1H), 7.77-7.74 (m, 2H),7.53-7.50 (m, 2H), 7.20 (s, 1H), 7.05-7.02 (m, 2H), 6.40 (t, J=5.2 Hz,1H), 4.69 (d, J=5.6 Hz, 2H), 4.67 (s, 2H), 3.97 (t, J=5.6 Hz, 2H), 3.92(s, 3H), 2.89 (t, J=5.6 Hz, 2H).

Example 117:2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-118)

Preparation ofN-(4-bromo-2-chloro-5-fluorobenzyl)-2-(tert-butyl)thiazole-5-carboxamide

To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanamine (427 mg,2.31 mmol) in 4 mL DMF were added 2-(tert-butyl)thiazole-5-carboxylicacid (500 mg, 2.10 mmol), HBTU (955 mg, 2.52 mmol) and DIEA (542 mg,4.20 mmol). The mixture was stirred at rt for 1.5 h. After diluted withwater (30 mL), the mixture was extracted with EtOAc (60 mL×2). Thecombined organic layer was dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography(EtOAc/petroleum ether=1/4) to give productN-(4-bromo-2-chloro-5-fluorobenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a pale yellow solid (540 mg, yield: 72%). ESI-MS (M+H)⁺: 405.0.

Synthesis of2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

A mixture ofN-(4-bromo-2-chloro-5-fluorobenzyl)-2-(tert-butyl)thiazole-5-carboxamide(240 mg, 0.60 mmol), Bis(pinacolato)diboron (156 mg, 0.60 mmol),4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (136 mg, 0.60mmol), Pd(dppf)Cl₂.CH₂Cl₂ (48 mg, 0.06 mmol), K₂CO₃ (246 mg, 1.80 mmol)in DMF (8 mL) and water (2 mL) was heated at 100° C. by microwave for 2h under nitrogen. The mixture was diluted with water (20 mL) andextracted with EtOAc (60 mL×2). The organic layer was dried (Na₂SO₄),filtered and concentrated. The residue was purified byprep-HPLC(CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give product2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a pale yellow solid (26 mg, yield: 9%). ESI-MS (M+H)⁺: 500.1. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.61 (s, 1H),9.25 (t, J=6.0 Hz, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 8.10 (d,J=7.2 Hz, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.36-7.34 (m, 1H), 7.13-7.10(m, 1H), 5.54 (d, J=5.6 Hz, 2H), 3.82 (s, 3H), 1.39 (s, 9H).

Example 118:N-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-119)

Synthesis ofN-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidewas similar to that of Example 1-72. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to get productN-(2-methyl-4-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamideas pale yellow oil (12 mg, yield: 27%). ESI-MS (M+H)⁺: 555.2. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.61 (d, J=5.6 Hz,1H), 8.07-7.94 (m, 3H), 7.96 (d, J=5.6 Hz, 1H), 7.88 (d, J=2.8 Hz, 1H),7.45-7.36 (m, 3H), 4.52 (s, 2H), 4.21 (s, 2H), 3.95-3.49 (m, 2H), 3.47(t, J=6.0 Hz, 4H), 3.45-3.35 (m, 2H), 3.10 (t, J=6.0 Hz, 4H), 2.90 (s,3H), 2.39 (s, 3H).

Example 119:N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-120)

Synthesis ofN-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 1. The crude product was purified bysilica gel column chromatography (EtOAc/petroleum ether=1/2 then EA) togive productN-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamideas a yellow solid (70 mg, yield: 56%). ESI-MS (M+H)⁺: 491.1. HPLC: (214nm: 94%, 254 nm: 96%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.48 (s, 1H), 8.89(t, J=5.2 Hz, 1H), 8.45 (d, J=4.4 Hz, 1H), 8.01-7.92 (m, 3H), 7.55 (d,J=8.0 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.25 (d, J=4.4 Hz,1H), 4.90 (s, 1H), 4.61 (s, 2H), 4.47 (d, J=5.6 Hz, 2H), 4.11 (t, J=5.6Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.75-3.71 (m, 2H), 2.84 (t, J=5.2 Hz,2H), 2.41 (s, 3H).

Example 120:3-isopropoxy-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-121)

Synthesis ofN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

Synthesis ofN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude waspurified through silica gel column chromatography (MeOH/DCM=1/30) togiveN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(130 mg, yield: 77%) as yellow oil. ESI-MS (M+H)⁺: 375.0.

Synthesis of3-isopropoxy-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude was purified through silica gel column chromatography(MeOH/DCM=1/20) to give3-isopropoxy-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(30 mg, yield: 18%) as a yellow solid. ESI-MS (M+H)⁺: 491.2. HPLC: (214nm: 95.69%, 254 nm: 97.57%). ¹H NMR (400 MHz, CD₃OD) δ: 8.48 (s, 1H),7.64 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.26 (d, J=7.6 Hz,1H), 6.14 (s, 1H), 4.32-4.29 (m, 1H), 4.26 (s, 2H), 4.08-4.01 (m, 4H),3.71-3.67 (m, 2H), 3.57 (s, 2H), 3.56-3.52 (m, 1H), 2.87 (t, J=6.0 Hz,2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.05 (d, J=6.0 Hz, 6H).

Example 121:(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-122)

Synthesis of (S)-tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g,5.3 mmol, 1.0 equiv) in pyridine (20 mL), TsCl (1.53 g, 7.95 mmol, 1.5equiv) was added. The mixture was stirred at rt for 12 h. Afterconcentrated, the residue was diluted with EtOAc (200 mL) and washedwith water (50 mL), HCl (1 N, 50 mL), brine (50 mL). The organic layerwas dried and concentrated to give (S)-tert-butyl3-(tosyloxy)pyrrolidine-1-carboxylate (1.3 g, yield: 71%) as a colorlessoil, which was used for next step without further purification. ESI-MS(M+Na)⁺: 364.0.

Synthesis of (R)-tert-butyl3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate(1.3 g, 3.8 mmol, 1.0 equiv) in NMP (10 mL), 4-nitro-1H-pyrazole (429mg, 3.8 mmol, 1.0 equiv) and Cs₂CO₃ (2.47 g, 7.6 mmol, 2.0 equiv) wereadded. The mixture was stirred at 90° C. for 12 h. After cooling down tort, the mixture was diluted with EtOAc (150 mL) and washed with water(50 mL×4). The organic layer was concentrated and purified by silica gelcolumn (PE:EA=3:1) to give (R)-tert-butyl3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (500 mg, yield:47%) as a yellow solid. ESI-MS (M+Na)+:305.1. ¹H NMR (400 MHz, CDCl₃) δ:8.17 (s, 1H), 8.09 (s, 1H), 4.91-4.89 (m, 1H), 3.89-3.85 (m, 2H),3.56-3.50 (m, 2H), 2.43-2.41 (m, 2H), 1.48 (s, 9H).

Synthesis of (R)-tert-butyl3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

A mixture of Pd/C (29 mg, 10% wt) and (R)-tert-butyl3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (290 mg, 1.1 mmol,1.0 equiv) in MeOH (5 mL) was stirred for at rt 12 h under hydrogenatmosphere (balloon pressure). The catalyst was filtered out and theresulting filtrate was concentrated to give target compound(R)-tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (260mg, yield: 100%) as a yellow oil. ESI-MS (M+H)⁺: 253.2.

Synthesis of (R)-tert-butyl3-(44(4-(44(2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

To a mixture of2-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(250 mg, 0.625 mmol, 1.0 equiv) and (R)-tert-butyl3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (189 mg, 0.75 mmol,1.2 equiv) in 1,4-dioxane (10 mL), Cs₂CO₃ (407 mg, 1.25 mmol, 2.0equiv), Pd₂(dba)₃ (57 mg, 0.063 mmol, 0.1 eq) and S-Phos (51 mg, 0.13mmol, 0.2 equiv) were added quickly under N₂. The mixture was stirred at120° C. for 12 h. After cooling down, the mixture was concentrated anddiluted with EtOAc (150 mL). The organic phase was washed with brine,dried and purified by prep-HPLC (Gradient: 5% B increase to 95% B, A:0.5% NH₃ in water, B: CH₃CN) to give (R)-tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(200 mg, yield: 53%) as a yellow solid. ESI-MS (M+H)⁺: 617.3

Synthesis of(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

A solution of (R)-tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(200 mg, 0.32 mmol, 1.0 equiv) in TFA/DCM (0.5 mL/2 mL) was stirred atrt for 1 h. The mixture was concentrated and purified by prep-HPLC(Gradient: 5% B increase to 95% B, A: 0.5% NH₃ in water, B: CH₃CN) togive(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(130 mg, yield: 77%) as a yellow solid. ESI-MS (M+H)⁺: 517.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H),7.86 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J=8.4 Hz,1H), 7.18 (s, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.34 (t, J=4.4 Hz, 1H),4.82-4.79 (m, 1H), 4.66 (d, J=5.2 Hz, 2H), 3.32-3.26 (m, 2H), 3.19-3.16(m, 1H), 3.02-2.95 (m, 1H), 2.44 (s, 3H), 2.35-2.15 (m, 2H), 1.45 (s,9H).

Example 122:(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-123)

To a solution of(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(170 mg, 0.32 mmol, 1.0 equiv) in MeOH (5 mL) was added (HCHO)_(n) (20mg, 0.64 mmol, 2.0 equiv) and NaBH₃CN (41 mg, 0.64 mmol, 2.0 equiv). Themixture was stirred at room temperature for 12 h. After concentrated,the residue was purified by pre-TLC (DCM:MeOH=10:1) to give(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(53 mg, yield: 30%) as a yellow solid. ESI-MS (M+H)⁺: 531.2. ¹H NMR (400MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 8.17 (s, 1H),7.97-7.95 (m, 2H), 7.65 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.20 (d, J=5.2Hz, 1H), 4.96-4.89 (m, 1H), 4.62 (s, 2H), 3.07-3.02 (m, 1H), 2.91-2.85(m, 2H), 2.71-2.65 (m, 1H), 2.65-2.54 (m, 4H), 2.41 (s, 3H), 2.25-2.19(m, 1H), 1.46 (s, 9H).

Example 123:(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-124)

Synthesis of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 121. The mixture was concentrated andpurified by prep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% TFA inwater, B: CH₃CN) to give(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(51 mg, yield: 64%) as a yellow solid. ESI-MS (M+H)⁺: 517.2. ¹H NMR (400MHz, CD₃OD) δ: 8.37 (d, J=6.0 Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H),8.01-7.99 (m, 2H), 7.79 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.39 (d, J=6.0Hz, 1H), 5.26-5.23 (m, 1H), 4.62 (s, 2H), 3.81-3.78 (m, 1H), 3.73-3.64(m, 2H), 3.55-3.49 (m, 1H), 2.61-2.51 (m, 1H), 2.48 (s, 3H), 2.44-2.37(m, 1H), 1.46 (s, 9H).

Example 124:(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-125)

Synthesis of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 122. The mixture was concentrated andpurified by silica gel column chromatography (DCM:MeOH=25:1 to 10:1) togive(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(76 mg, yield: 69%) as a yellow solid. ESI-MS (M+H)⁺: 531.2. ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H),7.94-7.91 (m, 2H), 7.74 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.18 (d, J=5.2Hz, 1H), 5.21-5.16 (m, 1H), 4.60 (s, 2H), 3.66-3.61 (m, 3H), 3.34-3.33(m, 1H), 2.92 (s, 3H), 2.71-2.61 (m, 1H), 2.45 (s, 3H), 2.39-2.32 (m,1H), 1.45 (s, 9H).

Example 125:(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-126)

Preparation of (S)-tert-butyl2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of 4-nitro-1H-pyrazole (1.0 g, 8.85 mmol) in THF (dry, 25mL), (S)-4-Boc-2-(hydroxymethyl)morpholine (1.9 g, 8.85 mmol, 1 equiv)and PPh₃ (3.5 g, 13.3 mmol, 1.5 equiv) were added respectively. DIAD(2.69 g, 13.3 mmol, 1.5 equiv) was added at 0° C. under nitrogen. Themixture was stirred at rt for 16 h. Then the solvent was removed. Theresidue was purified by silica gel chromatography column(EtOAc/petroleum ether=1:3) to give (S)-tert-butyl2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as yellowoil (1.0 g, yield: 69%). ESI-MS (M+H-56)⁺: 257.1. ¹H NMR (400 MHz,CD₃OD) δ: 8.54 (s, 1H), 8.13 (s, 1H), 4.58-4.56 (m, 1H), 4.38-4.25 (m,2H), 4.13-4.08 (m, 1H), 3.99-3.77 (m, 4H), 3.50-3.44 (m, 1H), 1.47 (s,9H).

Preparation of (S)-tert-butyl2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

Synthesis of (S)-tert-butyl2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate was similarto that of (R)-tert-butyl3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. After the catalystwas removed, the filtrate was concentrated and the crude title product(870 mg, yield: 96%) was used to next step without further purification.ESI-MS (M+H)⁺: 283.2.

Preparation of (S)-tert-butyl24(44(4-(44(2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

Synthesis of (S)-tert-butyl2-((4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylatewas similar to that of (R)-tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate.The residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give title product as a yellow solid (73 mg, yield:73%). ESI-MS (M+H)⁺: 647.3.

Preparation of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 121. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (58 mg, yield: 93%). ESI-MS (M+H)⁺: 547.3. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.34 (d, J=5.6 Hz,1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.99-7.97 (m, 2H), 7.75 (s, 1H), 7.45(d, J=7.6 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 4.61 (s, 2H), 4.38-4.29 (m,2H), 4.15-4.07 (m, 2H), 3.86-3.79 (m, 1H), 3.40-3.37 (m, 1H), 3.27-3.24(m, 1H), 3.14-3.10 (m, 1H), 2.89 (t, J=12.0 Hz, 1H), 2.46 (s, 3H), 1.46(s, 9H).

Example 126:(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-128)

Synthesis of(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamidewas similar to that of Example 121. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(R)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (103 mg, yield: 82%). ESI-MS (M+H)⁺: 547.3. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J=5.6 Hz,1H), 8.25 (s, 1H), 8.09 (s, 1H), 8.02-7.99 (m, 2H), 7.73 (s, 1H), 7.46(d, J=8.0 Hz, 1H), 7.35 (d, J=6.0 Hz, 1H), 4.63 (s, 2H), 4.36-4.33 (m,2H), 4.12-4.08 (m, 2H), 3.83-3.81 (m, 1H), 3.39-3.35 (m, 1H), 3.29-3.24(m, 1H), 3.12-3.10 (m, 1H), 2.88 (t, J=11.6 Hz, 1H), 2.49 (s, 3H), 1.47(s, 9H).

Example 127:(R)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-127)

Synthesis of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

A mixture ofN-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(223 mg, 0.5 mmol) and Cs₂CO₃ (487 mg, 1.5 mmol, 3 equiv) in DMF (5 mL)was stirred at rt for 1 h. Then (R)-oxiran-2-ylmethyl4-methylbenzenesulfonate (171 mg, 0.75 mmol, 1.5 equiv) was added. Themixture was stirred at rt for 30 min, then 80° C. for 2 h. After coolingdown to rt, the mixture was diluted with EA (80 mL), washed with brine,dried, concentrated. The crude was purified through prep-TLC(MeOH/DCM=1/20) to give(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamideas a yellow solid (65 mg, yield: 26%). ESI-MS (M+H)⁺: 504.1. ¹H NMR (400MHz, DMSO-d₆) δ: 9.54 (s, 1H), 9.10 (t, J=5.6 Hz, 1H), 8.47 (d, J=5.2Hz, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.95 (d, J=7.6 Hz,1H), 7.60 (s, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 4.50(d, J=5.6 Hz, 2H), 4.45 (d, J=15.6 Hz, 1H), 4.10 (dd, J=14.8, 6.4 Hz,1H), 2.81 (t, J=4.8 Hz, 1H), 2.58-2.56 (m, 1H), 2.42-2.41 (m, 4H), 1.39(s, 9H).

Synthesis of(R)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

A solution of(S)-2-(tert-butyl)-N-(2-methyl-4-(2-((1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(80 mg, 0.16 mmol) in 7N NH₃/MeOH (4 mL) was heated to 65° C. for 2 h ina sealed tube. Then the mixture was cooled to rt and the solvent wasremoved. The crude was purified through prep-HPLC (TFA/MeCN/Water as amobile phase) to give(R)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(62 mg, yield: 75%) as a yellow solid. ESI-MS (M+H)⁺: 521.2. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, CD₃OD) δ: 8.35 (d, J=5.6 Hz,1H), 8.26 (s, 1H), 8.08 (s, 1H), 8.04-8.01 (m, 2H), 7.77 (s, 1H),7.48-7.43 (m, 2H), 4.62 (s, 2H), 4.29-4.22 (m, 3H), 3.12-3.10 (m, 1H),2.88-2.83 (m, 1H), 2.48 (s, 3H), 1.46 (s, 9H).

Example 128:(S)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-129)

Synthesis of(S)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 127. After concentrated, the residue waspurified by prep-HPLC (MeOH/H₂O with 0.05% TFA as mobile phase) to givecompound(S)—N-(4-(2-((1-(3-amino-2-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(140 mg, yield: 92%) as a yellow solid. ESI-MS (M+H)⁺: 521.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.40 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.10 (s, 1H),8.01 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.45 (d, J=8.0 Hz,1H), 7.29 (d, J=5.6 Hz, 1H), 4.63 (s, 2H), 4.28-4.17 (m, 3H), 3.09-3.07(m, 1H), 2.85-2.81 (m, 1H), 2.49 (s, 3H), 1.47 (s, 9H).

Example 129:(S)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid (I-130)

Preparation of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-nitro-1H-pyrazol-1-yl)propanoate

To a solution of 4-nitro-1H-pyrazole (1.5 g, 13.2 mmol) in MeCN (30 mL)were added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate(2.7 g, 13.2 mmol) and K₂CO₃ (2.2 g, 15.8 mmol). The mixture was stirredat rt for 16 h. The solid was filtered off and the filtrate wasconcentrated and purified by column chromatography (silica, petroleumether/EtOAc=4:1) to give product (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-nitro-1H-pyrazol-1-yl)propanoate(1.44 g, yield: 21%) as a yellow liquid. ESI-MS (M+H-56)⁺: 259.0. ¹H NMR(400 MHz, CD₃OD) δ: 8.49 (s, 1H), 8.12 (s, 1H), 4.68-4.64 (m, 2H),4.49-4.43 (m, 1H), 3.77 (s, 3H), 1.40 (s, 9H).

Preparation of (S)-methyl3-(4-amino-1H-pyrazol-1-yl)-2-((tert-butoxycarbonyl)amino)propanoate

To a solution of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-nitro-1H-pyrazol-1-yl)propanoate(1.44 g, 4.6 mmol) in MeOH (20 mL) was added Pd/C (144 mg, 10% wt). Themixture was stirred at rt for 16 h under hydrogen atmosphere (balloonpressure). Then the mixture was filtered and the filtrate wasconcentrated in vacuo. The crude product (1.29 g. yield: 99%) was usedin the next step without further purification. ESI-MS (M+H)⁺: 285.1.

Preparation of(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid

Synthesis of(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid was similar to that of (R)-tert-butyl3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate.The residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid as a yellow solid (62 mg, yield: 56%). ESI-MS (M+H)⁺: 635.2.

Preparation of(S)-2-amino-3-(44(4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid

Synthesis of(S)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid was similar to that of Example 129. The crude product was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to give(S)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid as a yellow solid (90 mg, yield: 54%). ESI-MS (M+H)⁺: 535.2. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.55 (s, 1H),9.13 (t, J=5.6 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.00-7.95(m, 3H), 7.67 (br, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H),4.55-4.94 (m, 3H), 4.35-4.27 (m, 1H), 3.64-3.61 (m, 1H), 2.42 (s, 3H),1.39 (s, 9H).

Example 130:(S)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-131)

Preparation of (S)-tert-butyl(1-(44(4-(44(2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-3-hydroxypropan-2-yl)carbamate

To a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid (224 mg, 0.35 mmol) in 15 mL DME were added NMM (35 mg, 0.35 mmol),isobutyl carbonochloridate (53 mg, 0.39 mmol) at −15° C. The mixture wasstirred at −15° C. for 20 min. The solid was filtered off and NaBH₄ (27mg, 0.70 mmol) was added to the filtrate at −15° C. Then the mixture wasstirred at −15° C. for another 1 h. After diluted with water (4 mL), themixture was extracted with EtOAc (50 mL×2). The combined organic layerwas washed with H₂O (40 mL), dried (Na₂SO₄), filtered and concentrated.The crude product (300 mg, yield: 80%) was used in the next step withoutfurther purification.

Preparation of(S)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

Synthesis of(S)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 121. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(S)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a yellow solid (64 mg, yield: 25%). ESI-MS (M+H)⁺: 521.2. HPLC: (214nm: 97%, 254 nm: 97%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49 (s, 1H), 9.11(t, J=5.6 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 7.98-7.92 (m,3H), 7.56 (br, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H),4.72-4.71 (m, 1H), 4.92 (d, J=5.6 Hz, 2H), 4.11-4.07 (m, 1H), 3.92-3.87(m, 1H), 3.26-3.23 (m, 2H), 3.06-3.00 (m, 1H), 2.40 (s, 3H), 1.38 (s,9H).

Example 131:(R)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid (I-132)

Synthesis of(R)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid was similar to that of Example 129. The crude product was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% NH₃ as mobile phase) to give(R)-2-amino-3-(4-((4-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoicacid as a yellow solid (55 mg, yield: 54%). ESI-MS (M+H)⁺: 535.2. HPLC:(214 nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.54 (s, 1H),9.13 (br, 1H), 8.47 (d, J=4.4 Hz, 1H), 8.34 (s, 1H), 8.00-7.95 (m, 3H),7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), 4.51-4.47(m, 3H), 4.35-4.27 (m, 1H), 3.51-3.49 (m, 1H), 2.42 (s, 3H), 1.39 (s,9H).

Example 132:(R)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-133)

Synthesis of(R)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 130. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give(R)—N-(4-(2-((1-(2-amino-3-hydroxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamideas a yellow solid (15 mg, yield: 8%). ESI-MS (M+H)⁺: 521.2. HPLC: (214nm: 100%, 254 nm: 98%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49 (s, 1H), 9.10(t, J=5.6 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 7.98-7.92 (m,3H), 7.57 (br, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H),4.72-4.71 (m, 1H), 4.49 (d, J=5.2 Hz, 2H), 4.12-4.07 (m, 1H), 3.92-3.87(m, 1H), 3.28-3.20 (m, 2H), 3.06-3.02 (m, 1H), 2.40 (s, 3H), 1.38 (s,9H).

Example 133:2-(tert-butyl)-N-(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(I-134)

Synthesis of tert-butyl(6-(6-chloropyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate

Synthesis of tert-butyl(6-(6-chloropyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamatewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Obtained tert-butyl(6-(6-chloropyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(260 mg, yield: 68%) as a white solid. ESI-MS (M+H)⁺: 359.9. ¹H NMR (400MHz, CDCl₃) δ: 9.01 (s, 1H), 7.84-7.82 (m, 2H), 7.72 (s, 1H), 7.50 (d,J=8.4 Hz, 1H), 4.94-4.90 (m, 1H), 4.81-4.79 (m, 1H), 2.92-2.81 (m, 2H),2.11-2.04 (m, 1H), 1.88-1.74 (m, 3H), 1.49 (s, 9H).

Synthesis of tert-butyl(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate

Synthesis of tert-butyl(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamatewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.Obtained tert-butyl(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(100 mg, yield: 28%) as a yellow solid. ESI-MS (M+H)⁺: 476.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.74 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.09 (s, 1H),4.89-4.87 (m, 2H), 4.13 (t, J=6.0 Hz, 2H), 3.64 (s, 2H), 2.92 (t, J=5.6Hz, 2H), 2.85-2.82 (m, 2H), 2.50 (s, 3H), 2.08-2.05 (m, 1H), 1.84-1.80(m, 3H), 1.49 (s, 9H).

Synthesis of2-(tert-butyl)-N-(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamidewas similar to that of Example 1. Obtained2-(tert-butyl)-N-(6-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole-5-carboxamide(80 mg, yield: 70%) as a yellow solid. ESI-MS (M+H)⁺: 542.8. HPLC: (214nm: 99.33%, 254 nm: 97.39%). ¹H NMR (400 MHz, CD₃OD) δ: 8.60 (s, 1H),8.23 (s, 1H), 7.76-7.73 (m, 2H), 7.54 (s, 1H), 7.39 (d, J=8.0 Hz, 1H),6.26 (s, 1H), 5.35-5.32 (m, 1H), 4.13 (t, J=5.6 Hz, 2H), 3.69 (s, 2H),3.00-2.89 (m, 4H), 2.51 (s, 3H), 2.17-2.13 (m, 1H), 2.08-2.04 (m, 1H),1.96-1.91 (m, 2H), 1.46 (s, 9H).

Example 134:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(I-135)

Synthesis of tert-butyl4-(2-aminopyrimidin-4-yl)-2-methylbenzylcarbamate

To a solution of tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(347 mg, 1.0 mmol) in dioxane (8 mL) and H₂O (2 mL),4-chloropyrimidin-2-amine (129 mg, 1.0 mmol), Pd(dppf)Cl₂ (7.5 mg, 0.01mmol) and K₂CO₃ (414 mg, 3.0 mmol) were added under N₂. The mixture wasstirred at 100° C. for 2 h. Then the mixture was quenched with H₂O (60mL) and extracted with EA (60 mL×3). The organic layers were collected,concentrated. The residue was purified by column chromatography (silica,petroleum ether/EtOAc=1:1 to 1:2) to give tert-butyl4-(2-aminopyrimidin-4-yl)-2-methylbenzylcarbamate (257 mg, yield: 82%)as yellow solid ESI-MS (M+H)⁺: 315.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.30(d, J=4.8 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.34 (d, J=7.6Hz, 1H), 7.03 (d, J=5.6 Hz, 1H), 5.13 (br, 2H), 4.77 (br, 1H), 4.36 (d,J=6.0 Hz, 2H), 2.40 (s, 3H), 1.48 (s, 9H).

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide

A mixture of tert-butyl4-(2-aminopyrimidin-4-yl)-2-methylbenzylcarbamate (79 mg, 0.25 mmol) inTFA/DCM (6 mL, 1:1) was stirred at rt for 1 h. After removal ofsolvents, the residue was dissolved in DMF (4 mL),2-(tert-butyl)thiazole-5-carboxylic acid (47 mg, 0.25 mmol), HBTU (143mg, 0.38 mmol) and DIPEA (167 mg, 1.30 mmol) were added. The mixture wasstirred at rt for further 16 h. After diluted with water (60 mL), themixture was extracted with ethyl acetate (80 mL×2). The combinedextracts were evaporated and the residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-2-(tert-butyl)thiazole-5-carboxamide(62 mg, yield: 65%) as a white solid. ESI-MS (M+H)⁺: 382.2. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (s, 1H), 8.27 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 4.55(s, 2H), 2.42 (s, 3H), 1.42 (s, 9H).

Example 135:N-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamide(I-136)

Synthesis ofN-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamidewas similar to that of Example 134. The residue was purified byprep-HPLC (MeCN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)thiazole-5-carboxamideas a white solid (42 mg, yield: 26%). ESI-MS (M+H)⁺: 408.2. ¹H NMR (400MHz, DMSO-d₆) δ: 8.98 (d, J=8.4 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J=5.2Hz, 1H), 7.88 (s, 1H), 7.85 (dd, J=8.4, 1.6 Hz, 1H), 7.30 (d, J=8.0 Hz,1H), 7.10 (d, J=5.2 Hz, 1H), 6.66 (s, 2H), 5.22-5.20 (m, 1H), 2.86-2.84(m, 2H), 2.02-1.95 (m, 2H), 1.82-1.79 (m, 2H), 1.39 (s, 9H).

Example 136:N-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-137)

Synthesis ofN-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of Example 134. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to giveN-(6-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(50 mg, yield: 30%) as a white solid. ESI-MS (M+H)⁺: 405.1. HPLC: (214nm: 100.00%, 254 nm: 100.00%). ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (d, J=5.2Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H),7.18 (s, 1H), 7.05 (d, J=5.6 Hz, 1H), 6.03 (d, J=8.8 Hz, 1H), 5.40-5.38(m, 1H), 5.29 (br, 2H), 2.91-2.88 (m, 2H), 2.77 (t, J=5.6 Hz, 2H), 2.59(t, J=5.6 Hz, 2H), 2.20-2.14 (m, 1H), 1.94-1.77 (m, 7H).

Example 137:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxamide5,5-dioxide (I-138)

Synthesis of ethyl 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate

POCl₃ (2.12 g, 13.79 mmol) was dropwise added to DMF (1.13 g, 15.52mmol) in ice bath. DCM (20 mL) was added and the bath was removed whenthe reaction media appeared to be pasty. The reaction was kept at roomtemperature for 2 h. Then it was cooled to 0° C. again.Tetrahydro-thiopyran-4-one (1.0 g, 8.62 mmol) in 10 mL DCM was thendropwise added within 3 minutes. The reaction was kept at 0° C. for 2 h,dilute with DCM (250 ml) and then wash with ice cold saturated aqueoussodium acetate solution (100 mL). The organic layer was dried filtered,concentrated. The crude compound was dissolved in DCM (30 mL) then addedethyl 2-mercapto-acetate (1.66 g, 13.79 mmol) and 1 mL TEA. The mixturewas refluxed for 16 h. Then it was washed with water and dried overmagnesium sulfate. After filtered and concentrated, the residue waspurified by silica gel column chromatography (EtOAc/petroleumether=1:10) to give ethyl6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate (900 mg, yield:46%). ESI-MS (M+H)⁺: 229.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.47 (s, 1H),4.32 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.93 (t,J=5.6 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).

Synthesis of ethyl 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate5,5-dioxide

To a solution of ethyl6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate (300 mg, 1.32 mmol)in DCM (30 mL) was added m-CPBA (500 mg, 2.89 mmol) in portions. Themixture was stirred at room temperature for 2 h. After washing withsaturated aqueous sodium sulfite (40 mL), the organic phase wasevaporated and the residue was purified by pre-TLC (EtOAc/petroleumether=1:5) to give ethyl6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate 5,5-dioxide as abrown oil. ESI-MS (M+H)⁺: 261.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.42 (s,1H), 4.34 (q, J=7.2 Hz, 2H), 4.24 (s, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.30(t, J=6.4 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

Synthesis of 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid5,5-dioxide

To a solution ethyl 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate5,5-dioxide (180 mg, 0.692 mmol) in EtOH/H₂O (4:1, 20 mL) was addedsodium hydroxide (83 mg, 2.08 mmol). The mixture was refluxed for 2 h.After concentrated, the residue was diluted with water (10 mL),acidified with 1 N HCl to pH=4-5. The precipitate was collected byfiltration and dried to give6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid 5,5-dioxide (150mg, yield: 93%) as a white solid. ESI-MS (M+H)⁺: 233.0.

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxamide5,5-dioxide

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxamide5,5-dioxide was similar to that of Example 134, starting from6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid 5,5-dioxide. Theresidue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give compoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxamide5,5-dioxide (80 mg, yield: 29%) as a white solid. ESI-MS (M+H)⁺: 429.2.¹H NMR (400 MHz, DMSO-d₆) δ: 8.99 (t, J=6.0 Hz, 1H), 8.28 (d, J=5.6 Hz,1H), 7.90 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.32 (d, J=8.0Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 6.64 (s, 2H), 4.44 (d, J=5.6 Hz, 2H),4.43 (s, 2H), 3.46 (t, J=5.6 Hz, 2H), 3.35 (t, J=5.6 Hz, 2H), 2.37 (s,3H).

Example 138:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamide(I-139)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxamidewas similar to that of Example 134, starting from6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid. The residue waspurified by prep-HPLC (MeCN/H₂O with 0.05% NH₃.H₂O as mobile phase) togive title product as a white solid (40 mg, yield: 44%). ESI-MS (M+H)⁺:381.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (d, J=7.2 Hz, 1H), 8.08 (s, 1H),8.04 (dd, J=9.2, 1.6 Hz, 1H), 7.49-7.46 (m, 2H), 7.41 (s, 1H), 4.68 (s,2H), 4.61 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 2.91 (t, J=5.6 Hz, 2H), 2.48(s, 3H).

Example 139:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-140)

Synthesis of 5-tert-butyl 2-ethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate

Synthesis of 5-tert-butyl 2-ethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate was similar tothat of ethyl 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylate,starting from tert-butyl 4-oxopiperidine-1-carboxylate. The crudeproduct was purified by silica gel column chromatography(EtOAc/petroleum ether=1:10) to give 5-tert-butyl 2-ethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (4.1 g, yield:52%) as an yellow oil. ESI-MS (M+H)⁺: 312.1. ¹H NMR (400 MHz, CDCl₃) δ:7.49 (s, 1H), 4.48 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.72 (t, J=5.6 Hz,2H), 2.86 (t, J=5.6 Hz, 2H), 1.49 (s, 9H) 1.36 (t, J=7.2 Hz, 3H).

Synthesis of5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid

Synthesis of5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid was similar to that of6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid 5,5-dioxide. Thecrude product (500 mg, yield: 55%) was used in the next step withoutfurther purification. ESI-MS (M+H)⁺: 284.1.

Synthesis of tert-butyl2-((4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

Synthesis of tert-butyl2-((4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylatewas similar to that of Example 134. The crude tert-butyl2-((4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(200 mg, yield: 66%) was used in the next step without furtherpurification. ESI-MS (M+H)⁺: 480.2. ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d,J=5.2 Hz, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.37(d, J=8.0 Hz, 1H), 7.23 (s, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.07 (br, 1H),5.09 (br, 2H), 4.65 (d, J=5.6 Hz, 2H), 4.46 (s, 2H), 3.72 (t, J=5.6 Hz,2H), 2.85 (t, J=5.6 Hz, 2H), 2.43 (s, 3H), 1.48 (s, 9H).

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A mixture of tert-butyl2-((4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(200 mg, 0.418 mmol) in TFA/DCM (1:1, 20 mL) was stirred at roomtemperature for 1 h. After removal of solvent, the residue was adjustedto pH=8 with saturated aqueous sodium bicarbonate and purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givecompoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(100 mg, yield: 63%) as yellow solid. ESI-MS (M+H)⁺: 380.2. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d6) δ: 8.81 (t, J=6.0 Hz,1H), 8.28 (d, J=5.6 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.51(s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.6 Hz, 1H), 6.63 (s, 2H),4.44 (d, J=5.6 Hz, 2H), 3.72 (s, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.69 (t,J=5.6 Hz, 2H), 2.38 (s, 3H).

Example 140:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(I-141)

Synthesis of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Synthesis of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylatewas similar to that ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide.Crude ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (678mg, yield: 100%) was used in the next step without further purification.ESI-MS (M+H)⁺: 212.1.

Synthesis of ethyl5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

To a solution of ethyl4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (678 mg, 3.22mmol) in formic acid (30 mL) was added formalin (37%, 1.8 mL). Themixture was refluxed for 16 h. After cooling to rt, the mixture wasconcentrated under reduced pressure. The residue was adjusted to pH=8with 1 N NaOH and extracted with EtOAc (80 mL×2). The combined extractswere washed with brine, dried, purified with pre-TLC (EtOAc/petroleumether=1:1) to give ethyl5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (130 mg,yield: 18%) as an yellow oil. ESI-MS (M+H)⁺: 226.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.44 (s, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.51 (s, 2H), 2.95 (t,J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.49 (s, 3H), 1.35 (t, J=7.2 Hz,3H).

Synthesis of5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid

Synthesis of5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid wassimilar to that of 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylicacid 5,5-dioxide. The crude product (100 mg, yield: 88%) was used in thenext step without further purification. ESI-MS (M+H)⁺: 198.1.

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamidewas similar to that of Example 134. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givecompoundN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(53 mg, yield: 43%) as yellow solid. ESI-MS (M+H)⁺: 394.2. HPLC: (214nm: 100%, 254 nm: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.83 (t, J=5.2 Hz,1H), 8.28 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.51(s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 6.63 (s, 2H),4.45 (d, J=5.2 Hz, 2H), 3.38 (s, 2H), 2.82 (t, J=5.2 Hz, 2H), 2.64 (t,J=5.2 Hz, 2H), 2.38 (s, 3H), 2.35 (s, 3H).

Example 141:N-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-142)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of Example 134. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(4-(2-aminopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (120 mg, yield: 55%). ESI-MS (M+H)⁺: 379.1. HPLC: (214nm: 98%, 254 nm: 99%). ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d, J=5.2 Hz,1H), 7.85 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.20(s, 1H), 7.04 (d, J=5.6 Hz, 1H), 5.97 (br, 1H), 5.13 (br, 2H), 4.65 (d,J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.43 (s,3H), 1.86-1.71 (m, 4H).

Example 142:N-(4-(6-acetamidopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-143)

Synthesis ofN-(4-bromo-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

To a solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid(2.1 g, 12 mmol) in 30 mL DMF were added(4-bromo-2-methylphenyl)methanamine (2.4 g, 12 mmol), HBTU (5.4 g, 14.4mmol) and TEA (3.6 g, 36 mmol). The mixture was stirred at rt for 16 h.After diluted with water (100 ml), the mixture was extracted with EtOAc(100 mL×2). The combined organic layer was washed with H₂O (80 mL×2),dried (Na₂SO₄), filtered and concentrated. The residue was purified bysilica gel chromatography column (EtOAc/petroleum ether=1:5) to giveN-(4-bromo-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (3.8 g, yield: 86%). ESI-MS: 364.1 (M+H)⁺.

Synthesis ofN-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

To a solution ofN-(4-bromo-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(1 g, 2.7 mmol) and bis(pinacolato)diboron (740 mg, 3.2 mmol) in DMF (15mL) were added KOAc (544 mg, 5.4 mmol) and Pd(dppf)Cl₂DCM (112 mg, 0.14mmol) respectively. The mixture was stirred at 100° C. for 16 h underN₂. After cooling to rt, the mixture was diluted with water (80 mL) andextracted with EtOAc (80 mL×2). The organic layer was washed with brine(80 mL), dried (Na₂SO₄), filtered and concentrated. The residue waspurified by silica gel chromatography column (EtOAc/petroleum ether=1:4)to giveN-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (883 mg, yield: 76%). ESI-MS (M+H)⁺: 412.2. ¹H NMR (400MHz, CDCl₃) δ: 7.65 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.2 Hz,1H), 7.16 (s, 1H), 5.88 (br, 1H), 4.61 (d, J=5.2 Hz, 2H), 2.77 (t, J=6.0Hz, 2H), 2.56 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.86-1.76 (m, 4H), 1.34(s, 12H).

Synthesis ofN-(4-(6-acetamidopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

Synthesis ofN-(4-(6-acetamidopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of tert-butyl4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The crude productwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase)to giveN-(4-(6-acetamidopyrimidin-4-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a yellow solid (60 mg, yield: 41%). ESI-MS (M+H)⁺: 421.1. HPLC: (214nm: 99%, 254 nm: 97%). ¹H NMR (400 MHz, CDCl₃) δ: 8.82 (s, 1H), 8.52 (s,1H), 8.08 (br, 1H), 7.87 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.6Hz, 1H), 7.15 (s, 1H), 5.94 (br, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.72 (t,J=5.2 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.37 (s, 3H) 2.21 (s, 3H),1.79-1.71 (m, 4H).

Example 143: tert-butyl5-(2-aminopyrimidin-4-yl)-2-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)benzyl(methyl)carbamate(I-144)

Synthesis of 4-bromo-2-(bromomethyl)benzonitrile

To a solution of 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in 15 mLCCl₄ were added NBS (1.8 g, 10.2 mmol) and AIBN (340 mg, 2.08 mmol). Themixture was stirred at 80° C. for 16 h. After diluted with water (30mL), the mixture was extracted with DCM (50 mL×2). The combined organiclayer was washed with H₂O (30 mL×2), dried (Na₂SO₄), filtered andconcentrated. The crude product was used in the next step withoutfurther purification.

Synthesis of tert-butyl 5-bromo-2-cyanobenzyl(methyl)carbamate

To a solution of tert-butyl methylcarbamate (3.5 g, 26.4 mmol) in dryDMF (15 mL) was added NaH (0.64 g, 26.4 mmol) in ice bath. The mixturewas stirred at rt for 30 min, then a solution of4-bromo-2-(bromomethyl)benzonitrile (6.0 g, 22 mmol) in DMF (15 mL) wasadded. The mixture was stirred at rt for another 16 h. After dilutedwith water (50 mL), the mixture was extracted with EtOAc (80 mL×2). Thecombined organic layer was washed with H₂O (60 mL×2), dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (EA/PE=1:10) to give tert-butyl5-bromo-2-cyanobenzyl(methyl)carbamate as yellow solid (900 mg, yield:13%). ESI-MS (M+Na)⁺: 347.0. ¹H NMR (400 MHz, CDCl₃) δ: 7.54-7.51 (m,3H). 4.60-4.58 (m, 2H), 2.95-2.89 (m, 3H), 1.50-1.43 (m, 9H).

Synthesis of tert-butyl5-(2-aminopyrimidin-4-yl)-2-cyanobenzyl(methyl)carbamate

Synthesis of tert-butyl5-(2-aminopyrimidin-4-yl)-2-cyanobenzyl(methyl)carbamate was similar tothat of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate.The residue was purified by silica gel column chromatography(EtOAc/petroleum ether=1:5) to give tert-butyl5-(2-aminopyrimidin-4-yl)-2-cyanobenzyl(methyl)carbamate as a yellowsolid (1.6 g, yield: 64%). ESI-MS (M+H)⁺: 340.2. ¹H NMR (400 MHz, CDCl₃)δ: 8.33 (d, J=4.0 Hz, 1H), 7.98 (s, 1H), 7.94 (d, J=6.4 Hz, 1H), 7.70(d, J=8.0 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H), 4.64 (s, 2H), 2.91-2.89 (m,3H), 1.17-1.15 (m, 9H).

Synthesis of tert-butyl2-(aminomethyl)-5-(2-aminopyrimidin-4-yl)benzyl(methyl)carbamate

To a solution of tert-butyl5-(2-aminopyrimidin-4-yl)-2-cyanobenzyl(methyl)carbamate (1.6 g, 4.7mmol) in 30 mL MeOH were added Raney-Ni (160 mg) and NH₃.H₂O (3 mL). Themixture was stirred at rt for 16 h under hydrogen atmosphere. Thecatalyst was filtered off and the filtrate was concentrated to givetert-butyl2-(aminomethyl)-5-(2-aminopyrimidin-4-yl)benzyl(methyl)carbamate ascolorless oil (1.04 g, yield: 65%), which was used to next step withoutfurther purification. ESI-MS (M+H)⁺: 344.1.

Synthesis of tert-butyl5-(2-aminopyrimidin-4-yl)-24(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)benzyl(methyl)carbamate

Synthesis of tert-butyl5-(2-aminopyrimidin-4-yl)-2-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)benzyl(methyl)carbamatewas similar to that of Example I-7. The residue was purified by silicagel chromatography column (EtOAc/petroleum ether=1:4) to give tert-butyl5-(2-aminopyrimidin-4-yl)-2-((4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)methyl)benzyl(methyl)carbamateas a yellow solid (600 mg, yield: 51%). ESI-MS (M+H)⁺: 508.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.97 (d, J=6.8 Hz, 1H), 7.90(s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J=5.2 Hz, 1H),4.65 (s, 2H), 4.60 (s, 2H), 2.90 (s, 3H), 2.76 (t, J=5.2 Hz, 2H), 2.58(t, J=5.6 Hz, 2H), 1.87-1.82 (m, 4H), 1.47 (s, 9H).

Example 144:N-(4-(2-aminopyrimidin-4-yl)-2-((methylamino)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-145)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-((methylamino)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of Example 139. The crude product was purified byprep-HPLC (CH₃CN/H₂O as mobile phase) to giveN-(4-(2-aminopyrimidin-4-yl)-2-((methylamino)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (21 mg, yield: 58%). ESI-MS (M+H)⁺: 408.2. ¹H NMR (400MHz, DMSO-d₆) δ: 9.47-9.45 (m, 2H), 9.29 (s, 1H), 8.51 (d, J=5.2 Hz,1H), 8.39 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.95 (br, 1H), 7.60 (s, 2H),7.50-7.49 (m, 1H), 4.60 (d, J=5.2 Hz, 2H), 4.37 (s, 2H), 2.72-2.67 (m,5H) 2.56-2.55 (m, 2H), 1.75-1.73 (m, 4H).

Example 145:N-(4-(2-aminopyrimidin-4-yl)-2-((N-methylacrylamido)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(I-146)

Synthesis ofN-(4-(2-aminopyrimidin-4-yl)-2-((N-methylacrylamido)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidewas similar to that of Example 143. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to giveN-(4-(2-aminopyrimidin-4-yl)-2-((N-methylacrylamido)methyl)benzyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideas a white solid (10 mg, yield: 28%). ESI-MS (M+H)⁺: 462.2. ¹H NMR (400MHz, DMSO-d₆) δ: 8.91-8.89 (m, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.93 (d,J=8.0 Hz, 1H), 7.79-7.63 (m, 1H), 7.53-7.52 (m, 1H), 7.44-7.38 (m, 1H),7.05-6.97 (m, 1H), 6.91-6.70 (m, 2H), 6.22-6.19 (m, 1H), 5.78-5.63 (m,1H), 4.87-4.76 (m, 2H), 4.47-4.46 (m, 2H), 3.02-2.97 (m, 3H), 2.73 (t,J=5.2 Hz, 2H), 2.58 (t, J=4.8 Hz, 2H), 1.78-1.72 (m, 4H).

Example 146:2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

A mixture of2-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiazole-5-carboxamide(2.5 g, 6.0 mmol) and pyrimidine, 4,6-dichloro-(1.08 g, 7.24 mmol) in1,4-dioxane (25 mL) was degassed for 5 min. water (2.0 mL, 110 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (493 mg, 0.60 mmol) and potassium carbonate(1.67 g, 12.07 mmol) were then added, degassed for another 5 min, andthe reaction was heated at 110° C. for 2 h. After the reaction, themixture was cooled down, diluted with EtOAc, washed with water. Theorganic phase was dried, concentrated. The crude was purified on Si gel(EtOAc/heptane gradient from 10/90 to 100/0) to give the title compoundas a light yellow powder (1.82 g). LCMS: RT 1.75 min.; MH+401.1; ¹H NMR(400 MHz, DMSO-d₆) δ: 9.02-9.17 (m, 2H), 8.31 (d, J=12.80 Hz, 2H),8.02-8.15 (m, 2H), 7.40 (d, J=8.03 Hz, 1H), 4.50 (d, J=5.52 Hz, 2H),2.41 (s, 3H), 1.39 (s, 9H).

Synthesis of tert-butyl2-((6-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-4-yl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate(1-149) and2-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(1-148)

A mixture of2-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(200 mg, 0.50 mmol) and2-amino-7,8-dihydro-4H,6H-1,5,8a-triaza-azulene-5-carboxylic acidtert-butyl ester (164 mg, 0.65 mmol) in toluene (6.0 mL, 56 mmol) wasdegassed for 5 min, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (41mg, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05mmol) and sodium tert-butoxide (144 mg, 1.5 mmol) were then added,degassed for another 5 min, and the reaction was heated in microwave at100° C. for 1 h. The reaction was then cooled down, diluted with EtOAc,washed with water. The organics was dried, concentrated. The crude waspurified by ISCO (gradient DCM+1% to 10%2M NH₃/MeOH) to give tert-butyl2-((6-(4-((2-(tert-butyl)thiazole-5-carboxamido)methyl)-3-methylphenyl)pyrimidin-4-yl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate(1-149) as a light yellow powder (LCMS: RT 1.37 min.; MH+617.3) whichwas then dissolved in methylene chloride (4.0 mL, 62 mmol), treated withtrifluoroacetic acid (0.4 mL, 5 mmol). The reaction was stirred at RTfor 1 h. Remove the solvent. The crude was purified by ISCO (reversephase ACN/Water w/0.1% TFA gradient) to give2-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(1-148) as a yellow powder (48 mg, TFA salt). LCMS: RT 0.97 min.;MH+517.3; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.27 (br. s., 1H), 8.98-9.18 (m,3H), 8.70 (s, 1H), 8.33 (s, 1H), 7.72-7.87 (m, 2H), 7.40 (d, J=8.03 Hz,1H), 6.70 (br. s., 1H), 4.31-4.60 (m, 6H), 3.41 (br. s., 2H), 2.41 (s,3H), 2.02 (br. s., 2H), 1.39 (s, 9H).

Synthesis of2-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(I-147)

2-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide(30.0 mg, 0.06 mmol) was dissolved in methanol (1.0 mL) and formaldehyde(0.5 mL, 20 mmol). Sodium triacetoxyborohydride (62 mg, 0.29 mmol) wasthen added. The mixture was heated in microwave at 100° C. for 10 min.LCMS showed the complete of the reaction. The crude was purified by HPLCto give the title compound as a light yellow powder (16 mg, TFA salt).LCMS: RT 0.96 min.; MH+531.3; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.36 (br.s., 1H), 9.12 (t, J=5.65 Hz, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.70-7.89(m, 2H), 7.40 (d, J=8.03 Hz, 1H), 6.75 (br. s., 1H), 4.27-4.76 (m, 6H),3.36-3.71 (m, 2H), 2.82 (s, 3H), 2.41 (s, 3H), 1.85-2.28 (m, 2H), 1.39(s, 9H).

Example 147:1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

The synthesis of1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-150) was similar to that of Example 62, except1-tert-butyl-1H-pyrazole-4-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid to give the title compound as ayellow solid powder (45 mg). ESI-MS (M+H)+: 500.3. ¹H NMR (400 MHz,METHANOL-d₄) δ: 8.80 (s, 1H), 8.68 (t, J=5.65 Hz, 1H), 8.29 (s, 1H),7.98 (s, 1H), 7.67-7.81 (m, 2H), 7.53 (d, J=7.78 Hz, 1H), 6.61 (br. s.,1H), 4.61 (d, J=15.56 Hz, 4H), 4.47 (t, J=5.77 Hz, 2H), 3.87 (t, J=5.77Hz, 2H), 3.12 (s, 3H), 2.52 (s, 3H), 1.63 (s, 9H).

Example 148:3-(tert-butoxy)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of the3-(tert-butoxy)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(I-152) was the similar that of Example 19, except3-(tert-butoxy)azetidine was substituted for4-(trifluoromethyl)piperidine to give product as a solid (70 mg, yield:20%). ESI-MS (M+H)+: 450.3. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.48 (s, 1H),8.45 (d, J=5.02 Hz, 1H), 7.92 (s, 3H), 7.55 (br. s., 1H), 7.35 (d,J=8.28 Hz, 1H), 7.25 (d, J=5.02 Hz, 1H), 6.83 (t, J=5.65 Hz, 1H),4.38-4.55 (m, 1H), 4.22 (d, J=5.27 Hz, 2H), 4.03 (t, J=7.65 Hz, 2H),3.83 (s, 3H), 3.53-3.68 (m, 2H), 2.37 (s, 3H), 1.04-1.14 (m, 9H).

Example 149:2-(tert-butyl)-N-(4-(6-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide

Synthesis of2-(tert-butyl)-N-(4-(6-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide(I-151) was the similar to that of Example 62, starting from2-(3-amino-1H-pyrazol-1-yl)ethanol. ESI-MS (M+H)+: 492.2. ¹H NMR (400MHz, DMSO-d₆) δ: 9.99 (s, 1H), 9.14 (m, 1H), 8.65 (s, 1H), 8.35 (s.,1H), 7.85 (m, 2H), 7.62 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 6.40(brd, 1H), 4.92 (brd, 1H), 4.49 (d, J=5.2 Hz, 2H), 4.09 (t, J=7.65 Hz,2H), 3.75 (m, 2H), 2.40 (s, 3H), 1.39 (s, 9H).

Example 150:5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide

Synthesis of5-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide(1-153) was similar to that of Example 1, except5-(tert-butyl)isoxazole-3-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (39 mg, yield 50%). ESI-MS(M+H)⁺: 446. ¹H NMR (400 MHz, CDCl₃) δ: 7.86-7.97 (m, 3H), 7.72-7.81 (m,1H), 7.42-7.54 (m, 1H), 7.15-7.24 (m, 2H), 6.46 (s, 1H), 4.67-4.74 (m,2H), 3.94 (s, 3H), 2.49 (s, 3H), 1.38 (s, 9H).

Example 151:1-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-154) was similar to that of Example 1, except1-(tert-butyl)-1H-pyrazole-4-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (30 mg, yield 23%). ESI-MS(M+H)⁺: 446. ¹H NMR (400 MHz, METHANOL-d₄) δ: 7.97 (s, 1H), 7.94 (d,J=8.53 Hz, 1H), 7.86 (d, J=5.77 Hz, 2H), 7.59 (br. s., 1H), 7.34-7.41(m, 2H), 4.51 (s, 2H), 3.84 (s, 3H), 2.56 (s, 3H), 2.38 (s, 3H),1.48-1.52 (m, 9H).

Example 152:1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-3-carboxamide

Synthesis of1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-3-carboxamide(1-155) was similar to that of Example 1, except1-methyl-1H-pyrrole-3-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (35 mg, yield 50%). ESI-MS(M+H)⁺: 402. ¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=5.77 Hz, 1H), 7.79(br. m, 4H), 7.67 (s, 1H), 7.40 (d, J=8.28 Hz, 1H), 7.14 (d, J=5.77 Hz,1H), 4.55 (s, 2H), 4.06 (s, 3H), 3.83 (s, 3H), 2.39 (s, 3H).

Example 153:N-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

Synthesis ofN-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide(1-156) was similar to that of Example 1, except5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid wassubstituted for 2-(tert-butyl)thiazole-5-carboxylic acid. The crudeproduct was purified by prep-HPLC to give product as a solid (20 mg,yield 27%). ESI-MS (M+H)⁺: 443. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.21(d, J=5.77 Hz, 1H), 7.79 (d, J=4.02 Hz, 3H), 7.67 (s, 2H), 7.40 (d,J=8.28 Hz, 1H), 7.14 (d, J=5.77 Hz, 1H), 4.55 (s, 2H), 4.05 (t, J=5.52Hz, 2H), 3.83 (s, 3H), 3.28 (d, J=1.51 Hz, 2H), 2.84-2.96 (m, 3H), 2.56(s, 2H), 2.39 (s, 3H), 1.90-2.06 (m, 4H).

Example 154:1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(I-157) was similar to that of Example 1, except1-methyl-1H-pyrazole-4-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (90 mg, yield 60%). ESI-MS(M+H)⁺: 403. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.21 (d, J=6.27 Hz, 1H),7.90 (s, 1H), 7.79-7.86 (m, 2H), 7.77 (s, 1H), 7.71 (br. s., 1H), 7.40(d, J=8.28 Hz, 1H), 7.19 (d, J=6.02 Hz, 1H), 4.56 (s, 2H), 3.87 (br,s6H), 2.41 (s, 3H).

Example 155:1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-2-carboxamide

Synthesis of1-Methyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrrole-2-carboxamide(1-158) was similar to that of Example 1, except1-methyl-1H-pyrrole-2-carboxylic acid was substituted for2-(tert-butyl)thiazole-5-carboxylic acid. The crude product was purifiedby prep-HPLC to give product as a solid (40 mg, yield 30%). ESI-MS(M+H)⁺: 402. ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (br. s., 1H), 8.01 (s, 1H),7.90-7.95 (m, 4H), 7.76 (s, 1H), 7.50 (d, J=7.78 Hz, 1H), 7.23 (d,J=6.53 Hz, 1H), 6.77 (s, 1H), 6.63 (dd, J=1.38, 3.89 Hz, 1H), 6.24 (br.s., 1H), 6.12 (dd, J=2.76, 3.76 Hz, 1H), 4.65 (d, J=5.77 Hz, 2H), 3.97(s, 3H), 3.95 (s, 3H).

Example 156:N-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Synthesis ofN-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide(I-159) was similar to that of Example 1, except4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid wassubstituted for 2-(tert-butyl)thiazole-5-carboxylic acid. The crudeproduct was purified by prep-HPLC to give product as a solid (50 mg,yield 50%). ESI-MS (M+H)⁺: 443. ¹H NMR (400 MHz, METHANOL-d₄) δ: 8.35(d, J=5.77 Hz, 1H), 7.95-8.09 (m, 3H), 7.68 (s, 1H), 7.48 (d, J=8.03 Hz,1H), 7.40 (d, J=5.77 Hz, 1H), 6.50 (s, 1H), 4.64 (s, 2H), 4.18 (t,J=6.02 Hz, 2H), 3.94 (s, 3H), 2.87 (t, J=6.27 Hz, 2H), 2.50 (s, 3H),2.09 (d, J=5.52 Hz, 2H), 1.85-1.98 (m, 2H).

Example 157:3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

1. Synthesis ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

To a mixture of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(200 mg, 0.84 mmol) in DMF (5 mL), CDI (118 mg, 0.84 mmol) and TEA (340mg, 3.40 mmol) was added. The mixture was stirred at room temperaturefor 1 h followed by addition of 3-isopropoxyazetidine hydrochloride (127mg, 0.84 mmol). The resulting mixture was stirred at rt for another 12h. After diluting with CH₂Cl₂ (150 mL), the mixture was washed withbrine (50 mL×2). The organic phase was concentrated in vacuo and theresidue was purified by prep-HPLC (Gradient: 5% B increase to 95% B, A:0.5% NH₃ in water, B: CH₃CN) to giveN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(290 mg, yield: 74%) as a white solid. ESI-MS (M+1)⁺: 381.1. ¹H NMR (400MHz, CDCl₃) δ: 7.27-7.23 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 4.98-4.97 (m,1H), 4.41-4.32 (m, 2H), 4.16-4.11 (m, 2H), 3.89-3.84 (m, 2H), 3.64-3.58(m, 1H), 2.87-2.70 (m, 2H), 1.89-1.74 (m, 5H), 1.54-1.49 (m, 1H), 1.16(d, J=5.6 Hz, 6H).

2. Synthesis of3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

To a mixture ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(200 mg, 0.53 mmol) and bis(pinacolato)diboron (135 mg, 0.53 mmol) indry 1,4-dioxane (10 mL), KOAc (97 mg, 1.0 mmol), Pd(dppf)Cl₂.DCM (37 mg,0.05 mmol) was added. The mixture was stirred at 100° C. for 12 h underN₂. After cooling down,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (133 mg, 0.63mmol), K₂CO₃ (110 mg, 0.8 mmol) and water (1 mL) was added. Theresulting mixture was stirred at 100° C. for 12 h under N₂. Afterdiluting with EtOAc (150 mL), the mixture was washed with water (50mL×2). The organic phase was dried and concentrated in vacuo to afford aresidue was purified by silica gel column (CH₂Cl₂:MeOH=50:1) to give3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(60 mg, yield: 24%) as a yellow solid. ESI-MS (M+H)⁺: 476.3. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.89 (s, 1H), 7.81-7.78 (m, 2H),7.54 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H), 6.90 (s,1H), 5.10 (t, J=8.4 Hz, 1H), 4.47 (d, J=8.0 Hz, 1H), 4.40-4.34 (m, 1H),4.18-4.17 (m, 2H), 3.93-3.87 (m, 5H), 3.65-3.59 (m, 1H), 3.01-2.86 (m,2H), 1.90-1.79 (m, 5H), 1.60-1.50 (m, 1H), 1.17 (d, J=6.4 Hz, 6H).

Example 158:(R)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideand(S)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(160 mg) was subjected to the following SFC separation (AS-H (2×25 cm),20% methanol/CO2, 100 bar, 70 mL/min, 220 nm. inj vol.: 1 mL, 4 mg/mLmethanol) yielded 53.5 mg of peak-1 (chemical purity 95%, ee>99%) and69.4 mg of peak-2 (chemical purity 95%, ee>99%). Peak 1 was assigned as(S)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.20 min, m/z 476.30. ¹H NMR (300 MHz, CD₃OD) δ: 8.39 (d,J=5.29 Hz, 1H), 7.91-8.02 (m, 2H), 7.89 (s, 1H), 7.66 (s, 1H), 7.38 (d,J=7.93 Hz, 1H), 7.20 (d, J=5.29 Hz, 1H), 6.87 (d, J=7.93 Hz, 1H), 5.06(t, J=8.88 Hz, 1H), 4.38-4.55 (m, 1H), 4.13-4.32 (m, 2H), 3.90 (s, 3H),3.84 (d, J=8.69 Hz, 2H), 3.70 (td, J=6.09, 12.37 Hz, 1H), 3.39 (s, 3H),2.80-3.19 (m, 2H), 1.26-2.19 (m, 6H), 1.18 (s, 6H).

Peak 2 was assigned as(R)-3-isopropoxy-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.20 min, m/z 476.20. ¹H NMR (300 MHz, CD₃OD) δ: 8.39 (d,J=5.29 Hz, 1H), 7.91-8.02 (m, 2H), 7.89 (s, 1H), 7.66 (s, 1H), 7.38 (d,J=7.93 Hz, 1H), 7.20 (d, J=5.29 Hz, 1H), 6.87 (d, J=7.93 Hz, 1H), 5.06(t, J=8.88 Hz, 1H), 4.38-4.55 (m, 1H), 4.13-4.32 (m, 2H), 3.90 (s, 3H),3.84 (d, J=8.69 Hz, 2H), 3.70 (td, J=6.09, 12.37 Hz, 1H), 3.39 (s, 3H),2.80-3.19 (m, 2H), 1.26-2.19 (m, 6H), 1.18 (s, 6H).

Example 159:3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 157, except starting from3-tert-butoxyazetidine hydrochloride instead of 3-isopropoxyazetidinehydrochloride. The crude product was purified by silica gel column(CH₂Cl₂:MeOH=40:1) to give3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(60 mg, yield: 35%) as a yellow solid. ESI-MS (M+H)⁺: 490.4. ¹H NMR (400MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.89 (s, 1H), 7.81-7.78 (m, 2H),7.54 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H), 7.02 (s,1H), 5.09 (t, J=8.0 Hz, 1H), 4.53-4.48 (m, 2H), 4.18-4.16 (m, 2H), 3.91(s, 3H), 3.90-3.86 (m, 2H), 3.00-2.86 (m, 2H), 1.90-1.73 (m, 5H),1.58-1.51 (m, 1H), 1.19 (s, 9H).

Example 160:(R)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideand(S)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(90 mg) was subjected to the following SFC separation: (IA (2×25 cm),35% MeOH(0.1 DEA)/CO2, 100 bar, 70 mL/min, 220 nm. inj vol.: 1 mL, 9mg/mL methanol) and yielded 42 mg of peak-1 (chemical purity 99%,ee>99%) and 42 mg of peak-2 (chemical purity 99%, ee>99%). Peak 1 wasassigned as(R)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.27 min, m/z 490.30. ¹H NMR (400 MHz, CD₃OD-d4) δ: 8.40 (d,J=5.27 Hz, 1H), 7.94-8.05 (m, 2H), 7.90 (s, 1H), 7.67 (s, 1H), 7.39 (d,J=8.03 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 4.95-5.20 (m, 1H), 4.54-4.71(m, 1H), 4.14-4.33 (m, 2H), 3.91 (s, 3H), 3.82 (d, J=13.30 Hz, 2H),2.79-3.12 (m, 2H), 1.27-2.16 (m, 6H), 1.24 (s, 9H).

Peak 2 was assigned as(S)-3-(tert-butoxy)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.27 min, m/z 490.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (d, J=5.27Hz, 1H), 7.92-8.07 (m, 2H), 7.89 (s, 1H), 7.67 (s, 1H), 7.39 (d, J=8.03Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 6.85 (d, J=8.03 Hz, 0H), 4.94-5.17 (m,1H), 4.52-4.69 (m, 1H), 4.16-4.32 (m, 2H), 3.89 (br. s., 3H), 3.83 (dd,J=5.02, 13.80 Hz, 2H), 2.78-3.13 (m, 2H), 1.29-2.14 (m, 6H), 1.24 (s,9H).

Example 161:N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

1. The preparation ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

A mixture ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(1.6 g, 4.2 mmol), bis(pinacolato)diboron (1.2 g, 4.6 mmol), KOAc (848mg, 8.4 mmol) and Pd(dppf)Cl₂.DCM (171 mg, 0.21 mmol) in 1,4-dioxane (20mL) was stirred at 100° C. for 2 h under nitrogen. After the mixture wascooled to rt, 2,4-dichloropyrimidine (626 mg, 4.2 mmol), Pd(dppf)Cl₂.DCM(171 mg, 0.21 mmol), K₂CO₃(1.16 g, 8.4 mmol) and H₂O (5 mL) were addedand the resulting mixture was stirred at 100° C. for another 2 h. Themixture was diluted with EtOAc (200 mL), washed with water (80 mL×2),dried with Na₂SO₄ and concentrated in vacuo to afford a residue whichwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase)to giveN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamideas a white solid (1.1 g, yield: 57%). ESI-MS (M+H)⁺: 415.1. ¹H NMR (400MHz, CDCl₃) δ: 8.61 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=8.0 Hz,1H), 7.62 (d, J=5.2 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.09 (t, J=8.4 Hz,1H), 4.49-4.46 (m, 1H), 4.39-4.36 (m, 1H), 3.93-3.87 (m, 2H), 3.66-3.60(m, 1H), 3.50-3.48 (m, 1H), 3.03-2.89 (m, 2H), 1.93-1.84 (m, 4H),1.76-1.73 (m, 1H), 1.57-1.48 (m, 1H), 1.18 (d, J=6.4 Hz, 6H).

2. The preparation ofN-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

To a solution ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(130 mg, 0.32 mmol) in 1,4-dioxane (5 mL) were added1-ethyl-1H-pyrazol-4-amine (36 mg, 0.32 mmol), Pd₂(dba)₃ (29 mg, 0.032mmol), S-Phos (26 mg, 0.064 mmol) and Cs₂CO₃ (312 mg, 0.96 mmol). Themixture was stirred at 100° C. for 2 h. After diluted with water (50mL), the mixture was extracted with EtOAc (60 mL×2). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobilephase) to giveN-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamideas a yellow solid (129 mg, yield: 73%). ESI-MS (M+H)⁺: 490.0. ¹H NMR(400 MHz, CD₃OD) δ: 8.27 (d, J=4.8 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.55 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.09 (d,J=4.8 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.94 (t, J=8.4 Hz, 1H), 4.35-4.32(m, 1H), 4.16-4.04 (m, 4H), 3.79-3.71 (m, 2H), 3.60-3.55 (m, 1H),2.95-2.81 (m, 2H), 1.87-1.74 (m, 4H), 1.60-1.52 (m, 1H), 1.37 (t, J=7.2Hz, 3H), 1.29-1.18 (m, 1H), 1.07 (d, J=6.0 Hz, 6H).

Example 162:3-isopropoxy-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-isopropoxy-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (128 mg, yield: 71%). ESI-MS (M+H)⁺: 504.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.82-7.79 (m,2H), 7.55 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10-7.07 (m, 1H), 6.81 (d,J=8.0 Hz, 1H), 4.97-4.93 (m, 1H), 4.43-4.31 (m, 2H), 4.16-4.08 (m, 2H),3.79-3.71 (m, 2H), 3.61-3.55 (m, 1H), 2.96-2.81 (m, 2H), 1.87-1.77 (m,4H), 1.60-1.52 (m, 1H), 1.42 (d, J=6.8 Hz, 6H), 1.30-1.22 (m, 1H), 1.08(d, J=6.0 Hz, 6H).

Example 163:N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

1. The preparation ofN-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

Synthesis ofN-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamidewas similar to that of Example 161. The residue was purified by silicagel column chromatography (EtOAc/MeOH=15:1) to give product as a yellowsolid (150 mg, yield: 50%). ESI-MS (M+H)⁺: 620.0.

2. The preparation ofN-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

A mixture ofN-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(150 mg, 0.24 mmol) in HCl/Dioxane (10 mL) was stirred at rt for 1 h.After concentration in vacuo, the crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to giveN-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamideas a yellow solid (46 mg, yield: 38%). ESI-MS (M+H)⁺: 506.0. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=4.8 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.58 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.09 (d, J=4.8Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.94 (t, J=8.8 Hz, 1H), 4.37-4.31 (m,1H), 4.16-4.08 (m, 4H), 3.81-3.71 (m, 4H), 3.61-3.55 (m, 1H), 2.95-2.83(m, 2H), 1.89-1.74 (m, 4H), 1.60-1.52 (m, 1H), 1.30-1.18 (m, 1H), 1.08(d, J=6.0 Hz, 6H).

Example 164:(R)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamideand(S)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide

N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide(40 mg) was subjected to the following SFC separation (IA (2×25 cm), 30%methanol(0.1 DEA)/CO2, 100 bar, 60 mL/min, 280 nm. inj vol.: 0.75 mL, 4mg/mL methanol) yielded 16 mg of peak-1 (chemical purity 99%, ee>99%)and 14 mg of peak-2 (chemical purity 99%, ee>99%). Peak 1 was assignedas(S)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide:LCMS: Rt 1.09 min, m/z 506.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J=5.27Hz, 1H), 8.08 (s, 1H), 7.83-7.99 (m, 2H), 7.69 (s, 1H), 7.38 (d, J=8.09Hz, 1H), 7.20 (d, J=5.33 Hz, 1H), 5.06 (d, J=10.04 Hz, 1H), 4.38-4.52(m, 1H), 4.14-4.31 (m, 4H), 3.79-3.97 (m, 4H), 3.60-3.76 (m, 1H),2.82-3.10 (m, 2H), 1.27-2.16 (m, 6H), 1.18 (s, 6H). Peak 2 was assignedas(R)—N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide:LCMS: Rt 1.09 min, m/z 506.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.37 (br. s.,1H), 8.07 (s, 1H), 7.82-7.99 (m, 2H), 7.69 (s, 1H), 7.37 (d, J=8.03 Hz,1H), 7.19 (br. s., 1H), 5.05 (d, J=10.23 Hz, 1H), 4.46 (br. s., 1H),4.13-4.32 (m, 4H), 3.79-3.99 (m, 4H), 3.69 (dd, J=6.09, 8.53 Hz, 1H),2.79-3.13 (m, 2H), 1.30-2.13 (m, 6H), 1.18 (d, J=6.09 Hz, 6H).

Example 165:3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (47 mg, yield: 31%). ESI-MS (M+H)⁺: 520.0. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.2Hz, 1H), 4.96-4.94 (m, 1H), 4.37-4.31 (m, 1H), 4.19-4.08 (m, 4H),3.79-3.70 (m, 2H), 3.65 (t, J=5.2 Hz, 2H), 3.59-3.55 (m, 1H), 3.25 (s,3H), 2.96-2.87 (m, 2H), 1.89-1.76 (m, 4H), 1.60-1.52 (m, 1H), 1.30-1.23(m, 1H), 1.08 (d, J=6.0 Hz, 6H).

Example 166:3-isopropoxy-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-isopropoxy-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (75 mg, yield: 58%). ESI-MS (M+H)⁺: 546.0. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.6 Hz, 1H), 8.03 (s, 1H), 7.83-7.80 (m, 2H),7.57 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 4.97-4.93(m, 1H), 4.37-4.25 (m, 2H), 4.17-4.09 (m, 2H), 3.99-3.95 (m, 2H),3.79-3.71 (m, 2H), 3.61-3.55 (m, 1H), 3.52-3.46 (m, 2H), 2.96-2.82 (m,2H), 2.00-1.75 (m, 8H), 1.60-1.53 (m, 1H), 1.31-1.23 (m, 1H), 1.08 (d,J=6.8 Hz, 6H).

Example 167:3-(tert-butoxy)-N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(2-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (42 mg, yield: 40%). ESI-MS (M+H)⁺: 504.0. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J=8.0 Hz,1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.08 (d, J=5.6Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 4.94 (t, J=8.4 Hz, 1H), 4.52-4.46 (m,1H), 4.15-4.04 (m, 4H), 3.76-3.68 (m, 2H), 2.94-2.80 (m, 2H), 1.88-1.76(m, 4H), 1.58-1.55 (m, 1H), 1.37 (t, J=7.2 Hz, 3H), 1.27-1.18 (m, 1H),1.11 (s, 9H).

Example 168:3-(tert-butoxy)-N-(2-(2-((l-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(2-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (11 mg, yield: 10%). ESI-MS (M+H)⁺: 518.3. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.83-7.80 (m, 2H),7.55 (s, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 6.79 (d,J=8.0 Hz, 1H), 4.95-4.93 (m, 1H), 4.52-4.49 (m, 1H), 4.43-4.37 (m, 1H),4.16-4.08 (m, 2H), 3.77-3.69 (m, 2H), 2.93-2.85 (m, 2H), 1.88-1.76 (m,4H), 1.59-1.55 (m, 1H), 1.43 (d, J=6.8 Hz, 6H), 1.28-1.18 (m, 1H), 1.12(s, 9H).

Example 169:3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (41 mg, yield: 37%). ESI-MS (M+H)⁺: 534.1. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J=9.2 Hz,1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 4.96-4.93 (m, 1H), 4.54-4.48 (m, 1H), 4.19 (t, J=5.2 Hz, 2H),4.16-4.08 (m, 2H), 3.79-3.68 (m, 2H), 3.65 (t, J=5.2 Hz, 2H), 3.25 (s,3H), 2.96-2.83 (m, 1H), 1.92-1.77 (m, 4H), 1.60-1.56 (m, 1H), 1.28-1.18(m, 1H), 1.10 (s, 9H).

Example 170:(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideand(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(100 mg) was subjected to the following SFC separation (AS-H (2×15 cm),30% methanol(0.1 DEA)/CO2, 100 bar, 55 mL/min, 280 nm. inj vol.: 1.0 mL,5 mg/mL methanol) yielded 34.4 mg of peak-1 (chemical purity 99%,ee>99%) and 28.8 mg of peak-2 (chemical purity 99%, ee>99%). Peak 1 wasassigned as(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.27 min, m/z 534.3. ¹H NMR (400 MHz, CD₃OD) δ:0.37 (d, J=5.21Hz, 1H), 8.07 (s, 1H), 7.93 (d, J=8.09 Hz, 1H), 7.88 (s, 1H), 7.67 (s,1H), 7.37 (d, J=8.09 Hz, 1H), 7.18 (d, J=5.33 Hz, 1H), 5.05 (d, J=10.16Hz, 1H), 4.58 (br. s., 1H), 4.10-4.32 (m, 4H), 3.80 (s, 2H), 3.76 (d,J=5.40 Hz, 2H), 3.32 (s, 3H), 2.80-3.10 (m, 2H), 1.26-2.09 (m, 6H), 1.22(s, 9H). Peak 2 was assigned as(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide:LCMS: Rt 1.27 min, m/z 534.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J=5.15Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=8.03 Hz, 1H), 7.89 (s, 1H), 7.68 (s,1H), 7.38 (d, J=8.09 Hz, 1H), 7.20 (d, J=5.21 Hz, 1H), 5.05 (d, J=10.16Hz, 1H), 4.59 (br. s., 2H), 4.08-4.35 (m, 4H), 3.79-3.92 (m, 2H),3.69-3.76 (m, 2H), 3.36 (s, 3H), 2.78-3.12 (m, 2H), 1.26-2.09 (m, 6H),1.23 (s, 9H).

Example 171:3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

1. Synthesis ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butoxy)azetidine-1-carboxamide

Synthesis ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butoxy)azetidine-1-carboxamidewas similar to that ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The residue was purified by silica gel column (petroleumether/EtOAc=1:3) to giveN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butoxy)azetidine-1-carboxamide(2.9 g, yield: 50%) as a white solid. ESI-MS (M+1)⁺: 395.1. ¹H NMR (400MHz, CDCl₃) δ: 7.27-7.23 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 4.96 (t, J=7.6Hz, 1H), 4.51-4.45 (m, 1H), 4.38-4.36 (m, 1H), 4.15-4.10 (m, 2H),3.88-3.82 (m, 2H), 2.87-2.70 (m, 2H), 1.88-1.74 (m, 5H), 1.56-1.44 (m,1H), 1.18 (s, 9H).

2. The preparation of3-(tert-butoxy)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH asmobile phase) to give3-(tert-butoxy)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (720 mg, yield: 70%). ESI-MS (M+H)⁺: 429.1. ¹H NMR(400 MHz, CDCl₃) δ: 8.61 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.09 (t, J=8.0Hz, 1H), 4.50-4.47 (m, 2H), 4.16-4.13 (m, 1H), 3.91-3.87 (m, 2H),3.02-2.88 (m, 2H), 1.93-1.85 (m, 4H), 1.83-1.80 (m, 1H), 1.53-1.51 (m,1H), 1.19 (s, 9H).

3. The preparation of3-(tert-butoxy)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The residue was purified by silicagel column chromatography (EtOAc/MeOH=10:1) to give3-(tert-butoxy)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (160 mg, yield: 51%). ESI-MS (M+H)⁺: 634.0.

4. The preparation of3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

A mixture of3-(tert-butoxy)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(140 mg, 0.22 mmol) and SOCl₂ (26 mg, 0.22 mmol) in MeOH (10 mL) wasstirred at 70° C. for 1 h. After concentration, the crude product waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) togive3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (48 mg, yield: 37%). ESI-MS (M+H)⁺: 520.0. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.4 Hz,1H), 7.79 (s, 1H), 7.58 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.2Hz, 1H), 4.96-4.94 (m, 1H), 4.53-4.47 (m, 1H), 4.16-4.08 (m, 4H), 3.80(t, J=5.2 Hz, 2H), 3.77-3.68 (m, 2H), 2.95-2.83 (m, 2H), 1.89-1.74 (m,4H), 1.60-1.52 (m, 1H), 1.27-1.18 (m, 1H), 1.12 (s, 9H).

Example 172:3-(tert-butoxy)-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(2-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (57 mg, yield: 55%). ESI-MS (M+H)⁺: 560.0. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=4.8 Hz, 1H), 8.03 (s, 1H), 7.83-7.81 (m, 2H),7.57 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.10-7.09 (m, 1H), 4.97-4.95 (m,1H), 4.53-4.48 (m, 1H), 4.30-4.27 (m, 1H), 4.16-4.08 (m, 2H), 3.99-3.96(m, 2H), 3.77-3.69 (m, 2H), 3.52-3.46 (m, 2H), 2.97-2.82 (m, 2H),1.98-1.77 (m, 8H), 1.60-1.53 (m, 1H), 1.28-1.23 (m, 1H), 1.12 (s, 9H).

Example 173:3-(tert-butoxy)-N-(2-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 161. The residue was purified by prep-TLC(DCM/MeOH=10/1) to give3-(tert-butoxy)-N-(2-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(33 mg, yield: 41%) as a yellow solid. ESI-MS (M+H)⁺: 573.3. ¹H NMR (400MHz, CD₃OD) δ: 8.26 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.53 (d, J=7.6 Hz,1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.07 (d, J=5.2Hz, 1H), 4.94 (d, J=10.0 Hz, 1H), 4.52-4.46 (m, 1H), 4.15-4.00 (m, 3H),3.77-3.69 (m, 2H), 2.94-2.79 (m, 4H), 2.23 (s, 3H), 2.17-2.11 (m, 2H),2.06-1.85 (m, 7H), 1.82-1.72 (m, 1H), 1.61-1.52 (m, 1H), 1.30-1.24 (m,1H), 1.11 (s, 9H).

Example 174:N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide

1. The preparation ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide

A mixture of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-aminehydrochloride (1.5 g, 5.5 mmol), DIPEA (2.1 g, 16.5 mmol) and CDI (1.1g, 6.6 mmol) in DMF (20 mL) was stirred at rt for 0.5 h before additionof 3-isopropylpyrrolidine (746 mg, 6.6 mmol). The mixture was stirred atrt for 2 h, water (60 mL) was added and the mixture was extracted withEtOAc (100 mL×2) The combine organics were concentrated in vacuo andpurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) togiveN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamideas a while solid (760 mg, yield: 35%). ESI-MS (M+H)⁺: 379.1.

2. The preparation ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide

Synthesis ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamidewas similar to that ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The crude product was purified by silica gel column chromatography(petroleum ether/EtOAc=1:4) to giveN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamideas a yellow solid (480 mg, yield: 58%). ESI-MS (M+H)⁺: 413.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.65 (d, J=5.2 Hz, 1H), 7.99-7.92 (m, 3H), 7.43-7.40(m, 1H), 5.16-5.11 (m, 1H), 3.73-3.56 (m, 2H), 3.05-3.00 (m, 4H),2.14-2.10 (m, 4H), 2.02-1.86 (m, 6H), 1.75-1.53 (m, 2H), 1.39-1.33 (m,1H), 1.02-0.99 (m, 6H).

3. The preparation ofN-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide

To a solution ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamide(80 mg, 0.2 mmol) in 1-butanol (5 mL) were added1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-amine (48 mg, 0.2mmol) and TFA (cat). The mixture was stirred at 100° C. for 3 h. Afterconcentration, the crude product was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄OH as mobile phase) to giveN-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropylpyrrolidine-1-carboxamideas a yellow solid (35 mg, yield: 29%). ESI-MS (M+H)⁺: 504.0. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.58 (s, 1H), 7.29-7.26 (m, 1H), 7.09 (d, J=5.2 Hz,1H), 6.44-6.39 (m, 1H), 5.04-5.01 (m, 1H), 4.11 (t, J=5.2 Hz, 2H), 3.80(t, J=5.2 Hz, 2H), 3.63-3.46 (m, 2H), 3.28-3.21 (m, 1H), 2.94-2.87 (m,3H), 2.04-1.99 (m, 1H), 1.91-1.85 (m, 6H), 1.62-1.44 (m, 2H), 1.29-1.27(m, 1H), 0.91-0.89 (m, 6H).

Example 175:3-(tert-butoxy)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamidewas similar to that of Example 174. After concentration, the crudeproduct was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobilephase) to give3-(tert-butoxy)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideas a yellow solid (70 mg, yield: 29%). ESI-MS (M+H)⁺: 516.3. ¹H NMR (400MHz, CD₃OD) δ: 8.22 (d, J=5.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.75 (s,1H), 7.57 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 4.94(d, J=10.4 Hz, 1H), 4.51-4.48 (m, 1H), 4.16-4.09 (m, 2H), 4.05-4.01 (m,2H), 3.76-3.68 (m, 2H), 2.90-2.82 (m, 4H), 2.54-2.50 (m, 2H), 1.87-1.76(m, 4H), 1.57-1.54 (m, 1H), 1.27-1.23 (m, 1H), 1.11 (s, 9H).

Example 176:3-Isopropyl-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-isopropyl-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-isopropyl-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamideas a yellow solid (17 mg, yield: 17%). ESI-MS (M+H)⁺: 518.1. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.29-7.26 (m, 1H), 7.10 (d, J=5.2 Hz,1H), 5.06-5.00 (m, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.65 (t, J=5.2 Hz, 2H),3.58-3.46 (m, 2H), 3.30-3.24 (m, 1H), 3.24 (s, 3H), 2.98-2.84 (m, 3H),2.06-1.99 (m, 1H), 1.92-1.79 (m, 5H), 1.65-1.43 (m, 3H), 1.33-1.24 (m,1H), 0.92-0.89 (m, 6H).

Example 177:3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

1. The preparation ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)pyrrolidine-1-carboxamide

Synthesis ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)pyrrolidine-1-carboxamidewas similar to that ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The residue was purified by prep-HPLC (MeCN/H₂O with 0.05% NH₄OH asmobile phase from 5% to 95%) to giveN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)pyrrolidine-1-carboxamide(1.0 g, yield: 47%) as yellow solid. ESI-MS (M+H)⁺:393.1.

2. The preparation of3-(tert-butyl)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that ofN-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The crude was purified by prep-HPLC (MeCN/H₂O with 0.05% NH₄OH as mobilephase from 5% to 95%) to give3-(tert-butyl)-N-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(780 mg, yield: 72%) as yellow solid. ESI-MS (M+H)⁺: 427.2.

3. The preparation of3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that of Example 161. The residue was purified byprep-HPLC (MeCN/H₂O with 0.05% NH₄OH as mobile phase from 5% to 95%) togive3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(48 mg, yield: 42%) as yellow solid. ESI-MS (M+H)⁺:488.3. ¹H NMR (400MHz, CD₃OD) δ: 8.36 (d, J=5.6 Hz, 1H), 7.95-7.86 (m, 3H), 7.65 (s, 1H),7.39-7.36 (m, 1H), 7.17 (d, J=5.2 Hz, 1H), 5.15-5.10 (m, 1H), 3.87 (s,3H), 3.68-3.48 (m, 2H), 3.36-3.35 (m, 1H), 3.20-2.90 (m, 3H), 2.15-1.85(m, 6H), 1.75-1.67 (m, 2H), 1.38-1.33 (m, 1H), 0.98 (s, 9H).

Example 178:3-(tert-butyl)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

1. The preparation of3-(tert-butyl)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that of Example 161. The residue was purified byprep-HPLC (MeCN/H₂O with 0.05% NH₄OH as mobile phase from 5% to 95%) togive3-(tert-butyl)-N-(2-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(144 mg, yield: 65%) as yellow solid. ESI-MS (M+H)⁺:632.4.

2. The preparation of3-(tert-butyl)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that ofN-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The crude was purified through prep-HPLC (MeCN/H₂O with 0.05% NH₄OH asmobile phase from 5% to 95%) to give3-(tert-butyl)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(90 mg, yield: 76%) as a yellow solid. ESI-MS (M+H)⁺:518.3. ¹H NMR (400MHz, CD₃OD) δ: 8.25 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.83-7.77 (m, 2H),7.59 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 5.04 (t,J=10.4 Hz, 1H), 4.11 (t, J=5.2 Hz, 2H), 3.80 (t, J=5.2 Hz, 2H),3.58-3.38 (m, 2H), 3.22-3.20 (m, 1H), 3.10-2.81 (m, 3H), 2.02-1.77 (m,6H), 1.65-1.60 (m, 2H), 1.28-1.25 (m, 1H), 0.88 (s, 9H).

Example 179:3-(tert-butyl)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamidewas similar to that of Example 161 The residue was purified by prep-HPLC(MeCN/H₂O with 0.05% NH₄OH as mobile phase from 5% to 95%) to give3-(tert-butyl)-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-1-carboxamide(70 mg, yield: 47%) as a yellow solid. ESI-MS (M+H)⁺:532.3. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J=8.0 Hz,1H), 7.79 (d, J=1.6 Hz, 1H), 7.58 (s, 1H), 7.32-7.28 (m, 1H), 7.09 (d,J=5.2 Hz, 1H), 5.09-5.02 (m, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.66 (t, J=5.2Hz, 2H), 3.59-3.40 (m, 2H), 3.25 (s, 3H), 3.12-2.84 (m, 3H), 2.06-1.80(m, 6H), 1.67-1.59 (m, 2H), 1.30-1.20 (m, 1H), 0.90 (s, 9H).

Example 180:3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide

1. Preparation of 3-(3-Bromo-benzylamino)-propionic acid ethyl ester

To a solution of ethyl 3-aminopropanoate (46.0 g, 0.3 mol) and3-bromobenzaldehyde (55.5 g, 0.3 mol) in MeOH (1.2 L) were added Et₃N(60.7 g, 0.6 mol) and NaCNBH₃ (56.5 g, 0.9 mol) portion-wise. Theresulting mixture was stirred at rt for 4 h. The reaction mixture wasconcentrated in vacuo and the residue was diluted with water (600 mL).The mixture was extracted with EtOAc (3×500 mL). The combined organiclayer was washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give3-(3-bromo-benzylamino)-propionic acid ethyl ester (46.5 g, yield: 54%)as a light yellow oil. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.52 (s, 1H), 7.40(d, J=7.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.04 (q, J=7.2 Hz, 2H), 3.67 (s,2H), 2.69 (t, J=7.2 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 1.17 (t, J=6.9 Hz,3H).

2. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethylester (3)

To a solution of 3-(3-bromo-benzylamino)-propionic acid ethyl ester(45.6 g, 0.16 mol) in pyridine (500 mL) was added TosCl (61.0 g, 0.32mol) at rt. The reaction mixture was stirred at 120° C. for 16 h. Thesolvent was removed in vacuo to give the crude product. The crudeproduct was purified by column chromatography on silica gel (petroleumether:EtOAc=10:1 to 5:1) to afford3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethylester (61 g, yield: 88%) as a light yellow oil. ¹H NMR (DMSO-d₆, 300MHz): δ 7.74 (d, J=8.4 Hz, 2H), 7.49-7.41 (m, 4H), 7.31 (d, J=5.1 Hz,2H), 4.33 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.41(s, 3H), 2.36 (t, J=6.9 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H).

3. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethylester (60.0 g, 0.14 mol) in a mixed solvent of EtOH (600 mL) and H₂O (60mL) was added NaOH (11.2 g, 0.28 mol) portion-wise, the reactionsolution was stirred at 60° C. for 4 h. The reaction solution was cooledto 0° C. and acidified to pH=5 with concentrated HCl. The solvent wasconcentrated in vacuo to give a residue which was extracted with EtOAc(3×150 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated in vacuo to give3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g,yield: 78.6%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 12.28 (br,1H), 7.74 (d, J=8.1 Hz, 2H), 7.49-7.41 (m, 4H), 7.32 (d, J=5.1 Hz, 2H),4.33 (s, 2H), 3.29 (t, J=6.9 Hz, 2H), 2.41 (s, 3H), 2.27 (t, J=7.5 Hz,2H).

4. Preparation of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g,0.11 mol) in DCM (1000 mL) were added dropwise DMF (1 mL) and oxalylchloride (27.9 g, 0.22 mol) portion-wise. The reaction solution wasstirred at 55° C. for 2 h. The mixture was concentrated in vacuo to givethe crude 3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionylchloride (47.2 g, yield: 99%) as a black oil which was used in the nextstep without further purification.

5. Preparation of8-Bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one

To a solution of3-[(3-Bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.0g, 0.11 mol) in anhydrous DCM (1200 mL) was added AlCl₃ (29.3 g, 0.22mol) portion-wise at rt. The reaction mixture was stirred at 55° C. for2 h. The reaction mixture was poured into ice water (1.2 L) andextracted with DCM (500 mL). The organic layer was concentrated in vacuoto give the crude product. The crude product was purified by columnchromatography on silica gel (petroleum ether:EtOAc=5:1 to 2:1) toafford8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one(35 g, yield: 81%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.65(d, J=8.4 Hz, 3H), 7.60-7.51 (m, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.68 (s,2H), 3.42 (t, J=9.2 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 2.37 (s, 3H).

6. Preparation of[8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester

To a solution of8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one(32.0 g, 0.08 mol) in EtOH (600 mL) were added NH₄OAc (18.5 g, 0.24 mol)and NaCNBH₃ (14.9 g, 0.24 mol) portion-wise at rt. Then the reactionmixture was stirred at 95° C. for 16 h. The mixture was poured into icewater (500 mL) and then EtOH was removed in vacuo. The residue wasextracted with DCM (3×500 mL). The combined solvent was concentrated.The residue was redissolved in DCM (300 mL) and were added Et₃N (12.2 g,0.12 mol) and (Boc)₂O (34.6 g, 0.12 mol) at rt. The mixture was stirredat rt for 4 h and then concentrated in vacuo to give the crude product.The crude product was purified by column chromatography on silica gel(peteroleum ether:EtOAc=8:1 to 2:1) toafford[8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester (16.7 g, yield: 42%) as a white solid. ¹H NMR(DMSO_d₆, 300 MHz): δ 7.62-7.51 (m, 2H), 7.47 (d, J=9.9 Hz, 1H),7.41-7.34 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 4.81-4.74 (m, 1H), 4.53 (d,J=15.0 Hz, 1H), 4.28 (d, J=15.3 Hz, 1H), 3.64-3.57 (m, 1H), 3.41-3.30(m, 1H), 2.35 (s, 3H), 1.85-1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.36 (s,9H).

7. Preparation of8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine

A solution of[8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester (14.8 g, 0.03 mol) in HCl/EtOAc (150 mL) wasstirred at 25° C. for 4 h. The resulting solid was filtered and washedwith MeOH and Et₂O to give the product8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine(10.5 g, yield: 89%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.79(br, 3H), 7.64-7.58 (m, 3H), 7.53 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.15(d, J=8.4 Hz, 1H), 4.71-4.61 (m, 2H), 4.31 (d, J=15.3 Hz, 1H), 3.82 (d,J=18.3 Hz, 1H), 2.38 (s, 3H), 2.14-2.07 (m, 1H), 1.77-1.71 (m, 1H).LC-MS: m/z 395.0/397.0 [M+H]⁺.

8. Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine

A solution of8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine(2.00 g, 5.06 mmol) in HBr (33% solution in acetic acid, 20 mL) washeated at 50° C. for 12 h. After cooling to rt, the mixture was dilutedEtOAc (50 mL). The white solid was collected by filtration and dried invacuo to afford crude product8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (1.66 g, yield:82%), which was used directly in the next step. ESI-MS (M+H)⁺241.1. ¹HNMR (400 MHz, CD₃OD) δ: 7.72-7.55 (m, 2H), 7.18 (d, J=8.4 Hz, 1H),4.99-4.98 (m, 1H), 4.51 (d, J=14.4 Hz, 1H), 4.39 (d, J=14.4 Hz, 1H),3.62-3.49 (m, 2H), 2.38-2.24 (m, 1H), 2.16-2.00 (m, 1H).

9. Synthesis of tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

To a solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine(640 mg, 1.60 mmol) and TEA (490 mg, 4.8 mmol) in DCM (20 mL) was added(Boc)₂₀ (314 mg, 1.44 mmol). The mixture was stirred at rt for 1 h.After diluting with DCM (100 mL), the mixture was washed with brine (20mL×2). The organic phase was concentrated in vacuo and the residue waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) togive tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as acolorless oil (364 mg, yield: 67%). ESI-MS (M+H)⁺: 341.1.

10. Synthesis of tert-butyl8-bromo-5-(3-isopropoxyazetidine-1-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

To a solution of tert-butyl5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (300mg, 0.90 mmol) in DMF (4 mL) was added TEA (138 mg, 1.35 mmol) and CDI(219 mg, 1.35 mmol). After stirring at rt for 1 h, 3-isopropoxyazetidine(204 mg, 1.35 mmol) was added to the solution. The resulting solutionwas stirred for another 1 h. The mixture was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give tert-butyl8-bromo-5-(3-isopropoxyazetidine-1-carboxamido)-4,5-dihydro-1H-benzo[c]azepine-2-(3H)-carboxylateas white solid. (178 mg, yield: 42%). ESI-MS (M+H)+482.2.

11. Synthesis of Cert-butyl5-(3-isopropoxyazetidine-1-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

Synthesis of tert-butyl5-(3-isopropoxyazetidine-1-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylatewas similar to that of Example 157. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to givetert-butyl 5-(3-isopropoxyazetidine-1-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(120 mg, yield: 60%) as white solid. ESI-MS (M+H)+577.3. ¹H NMR (400MHz, CD₃OD) δ: 8.43 (d, J=5.2 Hz, 1H), 8.11-7.98 (m, 3H), 7.67-7.64 (m,1H), 7.49-7.45 (m, 1H), 7.25 (d, J=5.2 Hz, 1H), 5.27-5.24 (m, 1H),4.78-4.74 (m, 1H), 4.50-4.45 (m, 2H), 4.29-4.22 (m, 2H), 3.96-3.85 (m,6H), 3.74-3.68 (m, 1H), 3.38-3.33 (m, 1H), 2.00-1.91 (m, 2H), 1.44-1.31(m, 9H), 1.20 (d, J=6.4 Hz, 6H).

12. Synthesis of3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide

tert-Butyl 5-(3-isopropoxyazetidine-1-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate(120 mg, 0.21 mmol) was dissolved in TFA/DCM solution (1/1, 10 mL). Themixture was stirred at rt for 1 h. After concentration in vacuo, theresidue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O asmobile phase) to give3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamideas brown solid (70 mg, yield: 71%). ESI-MS (M+H)⁺: 477.3. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.88 (dd, J=8.0, 1.4 Hz, 1H),7.85 (s, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.06(d, J=5.6 Hz, 1H), 5.12 (d, J=9.2 Hz, 1H), 4.39-4.27 (m, 1H), 4.21-4.08(m, 2H), 3.99-3.87 (m, 2H), 3.85-3.71 (m, 5H), 3.63-3.50 (m, 1H),3.21-3.15 (m, 1H), 3.13-3.00 (m, 1H), 1.93-1.74 (m, 2H), 1.08 (d, J=6.0Hz, 6H).

13. Synthesis of3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide

To a solution of3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide(140 mg, 0.29 mmol) in DMF (6 mL) was added DIPEA (114 mg, 0.88 mmol)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (69 mg, 0.29 mmol).The mixture was stirred at 60° C. for 1 h. After diluting with water (20mL), the mixture was extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (20 mL×2), dried and concentratedin vacuo. The residue was purified by prep-HPLC (MeCN/Water with 0.05%NH₄OH) to give3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamideas a yellow solid (15 mg, yield: 9%). ESI-MS (M+H)⁺: 559.3. ¹H NMR (400MHz, CD₃OD) δ: 8.30 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.88 (s,1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.2Hz, 1H), 5.09-5.07 (m, 1H), 4.37-4.32 (m, 1H), 4.20-4.08 (m, 3H),3.96-3.93 (m, 1H), 3.78 (s, 3H), 3.76-3.71 (m, 2H), 3.59-3.56 (m, 1H),3.28-3.25 (m, 1H), 3.17-3.15 (m, 1H), 2.98-2.90 (m, 2H), 1.96-1.87 (m,1H), 1.72-1.69 (m, 1H), 1.07 (d, J=6.0 Hz, 6H).

Example 181:3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide

To a mixture of3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamide(80 mg, 0.16 mmol) and oxetan-3-one (60 mg, 0.81 mmol) in MeOH (5 mL)was added zinc chloride (114 mg, 0.81 mmol) and NaBH₃CN (30 mg, 0.5mmol). The mixture was stirred at rt for 4 h before addition of water (5mL). After concentration, the residue was extracted with EtOAc (40mL×2). The combined organic layers were washed with brine (120 mL×2),dried and concentrated in vacuo. The crude product was purified byprep-TLC (MeOH/EA=1/8) to give3-isopropoxy-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)azetidine-1-carboxamideas a yellow solid (45 mg, yield: 45%). ESI-MS (M+H)⁺: 533.2. ¹H NMR (400MHz, CD₃OD) δ: 8.35 (d, J=5.2 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.92 (s,1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.16 (d, J=5.2Hz, 1H), 5.13-5.10 (m, 1H), 4.69-4.66 (m, 1H), 4.61-4.54 (m, 3H),4.42-4.37 (m, 1H), 4.21-4.13 (m, 2H), 3.83 (s, 3H), 3.82-3.76 (m, 3H),3.73-3.68 (m, 2H), 3.64-3.61 (m, 1H), 2.97-2.94 (m, 1H), 2.80-2.74 (m,1H), 1.98-1.93 (m, 1H), 1.89-1.83 (m, 1H), 1.12 (d, J=6.0 Hz, 6H).

Example 182:3-(tert-butoxy)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)azetidine-1-carboxamide

1. The preparation of methyl 4-(3-bromophenoxy)butanoate

To a solution of 3-bromophenol (3.44 g, 20.0 mmol) and methyl4-bromobutanoate (4.32 g, 24.0 mmol) in DMF (20 mL) was added K₂CO₃(5.52 g, 40.0 mmol). The mixture was stirred at rt for 0.5 h and thenheated with stirring at 90° C. for 1 h. After diluting with ethylacetate (200 mL), the mixture was washed with water (50 mL×3), dried andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (petroleum ether: EtOAc/EA=10:1) to give methyl4-(3-bromophenoxy)butanoate as a white liquid (5.2 g, yield: 96%).ESI-MS (M+H)⁺: 273.1.

2. The preparation of 4-(3-bromophenoxy)butanoic acid

Synthesis of 4-(3-bromophenoxy)butanoic acid was similar to that of3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid. Thecrude product (4.8 g, yield: 98%) was used in next step without furtherpurification. ESI-MS (M+H)⁺: 259.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.24-7.20(m, 1H), 7.10-7.08 (m, 2H), 6.93 (d, J=9.6 Hz, 1H), 3.97 (t, J=6.4 Hz,2H), 2.35 (t, J=7.2 Hz, 2H), 1.92-1.88 (m, 2H).

3. The Preparation of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

Synthesis of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one was similar tothat of8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one.The crude product was purified by silica gel column chromatography(petroleum ether:EtOAc=4:1) to give8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one as a white solid (1.2 g,yield: 71%). ESI-MS (M+H)⁺: 241.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d,J=8.8 Hz, 1H), 7.27-7.23 (m, 2H), 4.25 (t, J=6.8 Hz, 2H), 2.89 (t, J=7.2Hz, 2H), 2.25-2.18 (m, 2H).

4. The preparation of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine

Synthesis of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine wassimilar to that of[8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamicacid tert-butyl ester. The crude product was purified by silica gelcolumn chromatography to give the desired product as a white solid (900mg, yield: 75%). ESI-MS (M+H)⁺: 225.1.

5. The preparation ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-3-(tert-butoxy)azetidine-1-carboxamide

Synthesis ofN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-3-(tert-butoxy)azetidine-1-carboxamidewas similar to that ofN-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide.The crude product was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OHas mobile phase) to giveN-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-3-(tert-butoxy)azetidine-1-carboxamideas a white solid (224 mg, yield: 50%). ESI-MS (M+H)⁺: 397.0. ¹H NMR (400MHz, CDCl₃) δ: 7.15-7.12 (m, 3H), 5.06-5.03 (m, 1H), 4.77-4.74 (m, 1H),4.44-4.41 (m, 1H), 4.34-4.31 (m, 1H), 4.09-4.04 (m, 2H), 3.81-3.69 (m,3H), 2.22-2.11 (m, 2H), 1.84-1.61 (m, 2H), 1.16 (s, 9H).

6. The preparation of3-(tert-butoxy)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)azetidine-1-carboxamidewas similar to that of Example 157. The residue was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)azetidine-1-carboxamideas a white solid (192 mg, yield: 69%). ESI-MS (M+H)⁺: 492.0. ¹H NMR (400MHz, CD₃OD) δ: 8.29-8.28 (m, 1H), 7.85 (s, 1H), 7.73 (d, J=8.0 Hz, 1H),7.63 (s, 1H), 7.53 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.07-7.05 (m, 1H),5.00 (d, J=8.0 Hz, 1H), 4.51-4.46 (m, 1H), 4.18-4.06 (m, 3H), 3.78 (s,3H), 3.74-3.68 (m, 3H), 2.00-1.87 (m, 3H), 1.81-1.72 (m, 1H), 1.10 (s,9H).

Example 183:3-(tert-butoxy)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

1. Synthesis of (E)-4-bromo-2-(2-(dimethylamino)vinyl)benzonitrile

A solution of 4-bromo-2-methylbenzonitrile (3.92 g, 20.00 mmol) in1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (8.2 mL, 40.00 mmol)was heated at 140° C. for 4 h. Then the reaction mixture was cooled downto rt and a yellow crystal precipitated. The solid was filtered off andwashed with petroleum ether, then dried to give(E)-4-bromo-2-(2-(dimethylamino)vinyl)benzonitrile (4.16 g, yield: 83%)as a yellow solid. ESI-MS (M+H)⁺: 251.0. ¹H NMR (400 MHz, CD₃OD) δ: 7.69(d, J=1.6 Hz, 1H), 7.33-7.28 (m, 2H), 7.05 (dd, J=8.4, 1.6 Hz, 1H), 5.22(d, J=13.2 Hz, 1H), 2.94 (s, 6H).

2. Synthesis of 4-bromo-2-(2-oxoethyl)benzonitrile

A mixture of (E)-4-bromo-2-(2-(dimethylamino)vinyl)benzonitrile (4.00 g,0.10 mmol) in 4N acetic acid aqueous solution (30 mL) was stirred at rtfor 4 h. Then the reaction mixture was filtered, and the cake was washedwith water and dried to give compound 4-bromo-2-(2-oxoethyl)benzonitrile(3.30 g, yield: 92%) as a white solid. ESI-MS (M+H)⁺: 223.9.

3. Synthesis of 2-(2-(aminomethyl)-5-bromophenyl)ethanol

Synthesis of 2-(2-(aminomethyl)-5-bromophenyl)ethanol was similar tothat of (4-bromo-2-methylphenyl)methanamine. Crude product2-(2-(aminomethyl)-5-bromophenyl)ethanol (2.05 g, yield: 100%) wasobtained as as a white solid. ESI-MS (M+H)⁺: 230.0.

4. Synthesis of Cert-butyl4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzylcarbamate

To a solution of 2-(2-(aminomethyl)-5-bromophenyl)ethanol (2.56 g, 11.2mmmol) in DCM (30 mL) were added Boc₂O (3.66 g, 16.8 mmol, 1.5 equiv)and TEA (3.4 g, 33.6 mmol, 3 equiv). The mixture was stirred at rt for 1h. The solvent was removed in vacuo. The crude was dissolved in EtOAc(60 mL), washed with water (30 mL×2), and brine (30 mL×2). The organiclayer was dried and concentrated in vacuo. The residue was dissolved inTHF (50 mL) and treated with TBSCl (2.38 g, 16 mmol, 1.5 equiv), DIPEA(4 g, 31.8 mmol, 2 equiv) and DMAP (129 mg, 1 mmol, 0.1 equiv). Themixture was stirred at rt for 16 h, diluted with EtOAc (100 mL), andwashed with water (60 mL×2) and brine (60 mL×2). The organic layer wasdried and concentrated in vacuo to give tert-butyl4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzylcarbamate as ayellow oil (4.5 g, 85% purity, and total yield: 80%). ESI-MS (M+H)⁺:444.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (s, 1H), 7.68 (d, J=7.6 Hz, 1H),7.34 (d, J=7.6 Hz, 1H), 5.16 (br, 1H), 4.41 (d, J=5.2 Hz, 2H), 3.91 (t,J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H), 1.51 (s, 9H), 0.87 (s, 9H), 0.001(s, 6H).

5. Synthesis of Cert-butyl2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

To a solution of tert-butyl4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl) benzylcarbamate (1 g,2.26 mmmol) in dioxane (15 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (635 mg, 2.5mmol, 1.1 equiv), Pd(dppf)Cl₂DCM (92 mg, 0.11 mmol, 0.05 equiv) and KOAc(664 mg, 6.78 mmol, 3 equiv). The mixture was heated to 110° C. for 1 hunder an atmosphere of nitrogen. After cooling to rt,4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (472 mg, 2.26mmol, 1.0 equiv), Pd(dppf)Cl₂DCM (92 mg, 0.11 mmol, 0.05 equiv), K₂CO₃(623 mg, 4.52 mmol, 2 equiv) and water (4 mL) were added. The mixturewas heated to 100° C. for 2 h. The mixture was cooled to rt and filteredthrough a Celite pad. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (EtOAc;petroleum ether=1/1) to give tert-butyl2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamateas a yellow solid (320 mg, total yield: 26%). ESI-MS (M+H)⁺: 539.1.

6. Synthesis of4-(4-(aminomethyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Synthesis of2-(2-(aminomethyl)-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethanolwas similar to4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amineand synthesis of4-(4-(aminomethyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminewas similar to that of tert-butyl4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzylcarbamate. Thecrude was purified by prep-(MeCN/Water with 0.05% NH₄OH as mobile phase)to give4-(4-(aminomethyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amineas a yellow solid (77 mg, total yield: 29%). ESI-MS (M+H)⁺: 439.2.

7. Synthesis of3-(tert-butoxy)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of Example 19. The reaction product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a yellow solid (75 mg, yield: 42%). ESI-MS (M+H)⁺: 480.3. ¹H NMR (400MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 8.02 (s,1H), 7.94 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J=8.0 Hz,1H), 7.21 (d, J=5.2 Hz, 1H), 4.60-4.54 (m, 1H), 4.45 (s, 2H), 4.17-4.13(m, 2H), 3.90 (s, 3H), 3.87 (t, J=6.8 Hz, 2H), 3.78-3.75 (m, 2H), 3.00(t, J=6.4 Hz, 2H), 1.19 (s, 9H).

Example 184:1-(tert-butyl)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 1. The reaction product was purifiedthrough silica gel column chromatography (MeOH/EA=1/10) to give1-(tert-butyl)-N-(2-(2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (40 mg, yield: 40%). ESI-MS (M+H)⁺: 475.2. ¹H NMR (400MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 8.01(s, 1H), 7.96-7.94 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.22(d, J=5.2 Hz, 1H), 4.67 (s, 2H), 3.92-3.88 (m, 5H), 3.06 (t, J=6.8 Hz,2H), 1.60 (s, 9H).

Example 185:1-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one

1. Synthesis of methyl5-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(tert-butyl)-1H-pyrazole-4-carboxylate

To a solution of CDI (972 mg, 6.0 mmol) in THF (18 mL) was addedN-Boc-3-aminylpropanoic acid (945 mg, 5 mmol). The mixture was stirredat rt for 1 h. Then a well homogenized and powdered solid mixture ofMgCl₂ (475 mg, 5 mmol) and potassium hydrogen methyl malonate (1.56 g,10 mmol) were added. The mixture was stirred at rt for 16 h. The solventwas removed and the crude was dissolved in EtOAc (80 mL), washed withKHSO₄ (1M, 20 mL×2) and brine (20 mL). The organic layer was dried andconcentrated in vacuo. The crude product was dissolved in DCM (16 mL)and DMF-DMA (773 mg, 6.5 mmol) was added. The mixture was stirred at rtfor 6 h. The solvent was removed and the crude material was dissolved inisopropanol (10 mL) and treated with tertbutylhydrazine (682 mg, 5.5mmol). The mixture was stirred at reflux for 3 h. After cooling to rt,the solvent was removed. The crude was dissolved in EtOAc (60 mL),washed with brine (20 mL×2). The organic layer was dried andconcentrated in vacuo. The crude was purified by silica gel columnchromatography (EtOAc/petroleum ether=1/4) to give methyl5-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(tert-butyl)-1H-pyrazole-4-carboxylate as yellow oil (250mg, three steps yield: 15%). ESI-MS (M+H)⁺: 326.2.

2. Synthesis of5-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-6,7-dihydro-1H-pyrazolo[4,3-e]pyridin-4(5H)-one

To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(tert-butyl)-1H-pyrazole-4-carboxylate (500 mg, 1.54mmol) in DCM (4 mL) was added TFA (4 mL). The mixture was stirred at rtfor 1 h. The mixture was concentrated, the crude was dissolved in CH₂Cl₂(10 mL) and 4-bromo-2-methylbenzaldehyde (370 mg, 1.87 mmol) was added.The mixture was stirred at rt for 10 min, then sodiumtriacetoxyborohydride (1.63 g, 7.7 mmol) was added. The mixture wasstirred at rt for 16 h, diluted with DCM (60 mL), washed with brine anddried over Na₂SO₄, filtered and concentrated in vacuo to afford a cruderesidue which was was heated to 100° C. for 2 h. The residue waspurified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) togive5-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-oneas a white solid (116 mg, yield: 20%). ESI-MS (M+H)⁺: 376.1.

3. Synthesis of1-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one

Synthesis of1-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-onewas similar to that of Example 13. The reaction produce was purifiedthrough silica gel column chromatography (MeOH/DCM=1/15) to give1-(tert-butyl)-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-oneas a yellow solid (80 mg, yield: 55%). ESI-MS (M+H)⁺: 471.3. ¹H NMR (400MHz, CD₃OD) δ: 8.41 (d, J=5.2 Hz, 1H), 7.99-7.95 (m, 3H), 7.80 (s, 1H),7.64 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 4.80 (s,2H), 3.89 (s, 3H), 3.60 (t, J=6.8 Hz, 2H), 3.25 (t, J=6.8 Hz, 2H), 2.44(s, 3H), 1.64 (s, 9H).

Example 186:1-(tert-butyl)-N-(4-(6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

1. The preparation of(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)methanamine

A mixture of tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (240 mg, 0.72 mmol)in TFA/DCM (8 mL, 1:1) was stirred at rt for 1 h. Then the solvent wasremoved in vacuo and the crude product (150 mg, yield: 89%) was used inthe next step without further purification.

2. The preparation of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

To a solution of (4-(6-chloropyrimidin-4-yl)-2-methylphenyl)methanamine(150 mg, 0.64 mmol) and acid (118 mg, 0.70 mmol) in DMF (5 mL) wereadded HATU (292 mg, 0.77 mmol) and DIPEA (247 mg, 1.92 mmol). Themixture was stirred at rt for 2 h. After diluting with water (60 mL),the mixture was extracted with EtOAc (80 mL×2). The combined organiclayers were dried and concentrated in vacuo to afford a crude productwhich was purified by silica gel column chromatography (petroleumether:EtOAc=1:2) to give1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamideas a white solid (230 mg, yield: 93%). ESI-MS (M+H)⁺: 384.1.

3. The Preparation of5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate

To a solution of pyrrolidine-2-carboxylic acid (17.2 g, 150 mmol) andsodium nitrite (14.5 g, 210 mmol) in water (100 mL) was slowly added HCl(7.6 g, 200 mmol) at 0° C. The mixture was stirred at rt for 16 h,diluted with water (100 mL), and extracted with diethyl ether (100mL×2). The combined organic phase was dried and concentrated in vacuo toafford a residue which was taken up in PhCH₃ (50 mL). The solution wastreated with trifluoroacetic anhydride (47.3 g, 230 mmol) and stirred atrt for 16 h. The mixture was concentrated and the crude product waspurified by silica gel column chromatography (DCM/MeOH=10:1) to give5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate as a brownliquid (17.0 g, yield: 90%). ESI-MS (M+H)⁺: 127.1.

4. The preparation of methyl5,6-dihydro-4H-pyrrolo[1,2-c]pyrazole-2-carboxylate and methyl5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate

To a solution of5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate (9.4 g, 75mmol) in xylene (150 mL) was added methyl propiolate (18.9 g, 225 mmol).The mixture was stirred at 125° C. for 16 h. After concentration, thecrude product was purified by silica gel column chromatography(petroleum ether:EtOAc=5:1) to give a mixture of methyl5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate and methyl5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate as a yellow liquid(7.9 g, yield: 35%). ESI-MS (M+H)⁺: 167.1.

5. The preparation of 5,6-dihydro-4H-pyrrolo[1,2-h]pyrazole-2-carboxylicacid and 5,6-dihydro-4H-pyrrolo[1,2-h]pyrazole-3-carboxylic acid

To a solution of methyl5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate and methyl5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (3.5 g, 21.0 mmol)in MeOH (50 mL) was added NaOH (2.5 g, 63.0 mmol) and stirred at 50° C.for 5 h. Water (50 mL) was added, the mixture was adjusted to pH=6 withconcentrated HCl, extracted with EtOAc (100 mL×2), dried andconcentrated in vacuo to afford the crude product (2.2 g, yield: 69%)which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ: 7.90 (s, 1H), 3.09 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2Hz, 2H), 2.22-2.15 (m, 2H).

6. The preparation of ethyl(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)carbamate and ethyl(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)carbamate

To a solution of the above mixture (1.0 g, 6.6 mmol) in dioxane (20 mL)was added DIPEA (2.5 g, 19.8 mmol) and DPPA (1.8 g, 6.6 mmol) andstirred at rt for 2 h. EtOH (10 mL) was added and the mixture was heatedto 110° C. for 2 h. The solvent was removed in vacuo, the crude productwas purified by silica gel column chromatography (petroleumether:EtOAc=1:3) to give a white solid. The solid was suspended in MeOH(15 mL), filtered, and the filtrate was concentrated in vacuo to give(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)carbamate (300 mg, yield:23%) as a white solid. The white precipitate is ethyl(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)carbamate (120 mg, yield:9%). ESI-MS (M+H)⁺: 196.1.

7. The Preparation of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-amine

To a solution of ethyl(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)carbamate (130 mg, 0.67 mmol)in EtOH (20 mL) was added NaOH (1.3 g, 33.3 mmol). The mixture wasstirred at 90° C. for 16 h. After concentration, the mixture wasdissolved in water (50 mL) and extracted with DCM (50 mL×2). Thecombined organic layers were dried, concentrated in vacuo to afford thecrude product (31 mg, yield: 33%) which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ: 7.18 (s, 1H),4.06 (t, J=7.2 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.60-2.53 (m, 2H).

8. The Preparation of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine

Synthesis of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine was similar tothat of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-amine. The crude product(85 mg, yield: 90%) was used in the next step without furtherpurification.

9. The Preparation of1-(tert-butyl)-N-(4-(6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(4-(6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 171. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give1-(tert-butyl)-N-(4-(6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamideas a white solid (30 mg, yield: 41%). ESI-MS (M+H)⁺: 471.2. ¹H NMR (400MHz, CD₃OD) δ: 8.47 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H),7.65 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.04 (s,1H), 4.48 (s, 2H), 3.99 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H),2.50-2.46 (m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).

Example 187:3-(tert-butyl)-N-(4-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(4-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)pyrrolidine-1-carboxamidewas similar to that of Example 174. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butyl)-N-(4-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)pyrrolidine-1-carboxamideas a yellow solid (27 mg, yield: 31%). ESI-MS (M+H)⁺: 474.1. ¹H NMR (400MHz, CD₃OD) δ: 8.22 (d, J=5.2 Hz, 1H), 7.79-7.78 (m, 2H), 7.57 (s, 1H),7.28 (d, J=7.6 Hz, 1H), 7.08 (d, J=5.2 Hz, 1H), 4.36-4.26 (m, 2H), 4.03(t, J=7.2 Hz, 2H), 3.67 (t, J=8.8 Hz, 1H), 3.47 (t, J=8.8 Hz, 1H),3.18-3.15 (m, 1H), 2.83 (t, J=7.2 Hz, 2H), 2.56-2.49 (m, 2H), 2.31 (s,3H), 2.04-2.00 (m, 1H), 1.84-1.79 (m, 1H), 1.64-1.59 (m, 1H), 0.80 (s,9H).

Example 188:cis-4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid

1. Synthesis of methyl4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate

Synthesis of methyl4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylatewas similar to that of Example 1. Methyl4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate(160 mg, yield: 73%) was obtained as a yellow solid. ESI-MS (M+H)⁺:571.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 8.05 (s, 1H),7.99 (s, 1H), 7.89-7.78 (m, 3H), 7.53 (s, 1H), 7.41 (d, J=8.0 Hz, 1H),7.14 (s, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.08 (t, J=5.2 Hz, 1H), 4.65 (d,J=5.6 Hz, 2H), 4.18-4.16 (m, 1H), 3.70 (s, 3H), 2.68-2.67 (m, 1H), 2.44(s, 3H), 2.26-2.22 (m, 2H), 2.09-2.06 (m, 2H), 1.84-1.67 (m, 4H), 1.60(s, 9H).

2. Synthesis oftrans-4-(44(4-(44(1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid

To a mixture of methyl4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylate(160 mg, 0.28 mmol) in MeOH (5 mL) and H₂O (3 mL), NaOH (22 mg, 0.56mmol) was added. The mixture was stirred at 65° C. for 1 h. Afterremoval of MeOH, the mixture was diluted with water (5 mL) and acidifiedto pH=5 with HCl (1 N), the precipitate was collected by filtration andpurified by prep-HPLC (Gradient: 5% B increase to 95% B, A: 0.5% TFA inwater, B: CH₃CN) to givetrans-4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (30 mg, yield: 19%) as a yellow solid andcis-4-(4-((4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexanecarboxylicacid (77 mg, yield: 49%) as a yellow solid. ESI-MS (M+H)⁺:557.3. trans-A¹H NMR (400 MHz, CD₃OD) δ: 8.36-8.34 (m, 1H), 8.21 (s, 1H), 7.98 (s,1H), 7.93 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.57-7.56 (m, 2H), 7.48 (d,J=8.0 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 4.62 (s, 2H), 4.19-4.13 (m, 1H),2.49 (s, 3H), 2.43-2.35 (m, 1H), 2.30-2.20 (m, 4H), 1.91-1.78 (m, 2H),1.72-1.66 (m, 2H), 1.62 (s, 9H). cis-B ¹H NMR (400 MHz, CD₃OD) δ:8.36-8.34 (m, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 8.00-7.99 (m, 1H),7.95-7.93 (m, 2H), 7.69 (s, 1H), 7.54-7.50 (m, 1H), 7.26 (d, J=6.0 Hz,1H), 4.62 (s, 2H), 4.24-4.18 (m, 1H), 2.72-2.71 (m, 1H), 2.50 (s, 3H),2.31-2.27 (m, 2H), 2.10-2.02 (m, 4H), 1.81-1.73 (m, 2H), 1.63 (s, 9H).

Example 189:5-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide

1. Synthesis of tert-butyl4-(4-((4-methoxypyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of 2-chloro-4-methoxypyrimidine (970 mg, 6.7 mmol), tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.8 g, 6.77 mmol),S-phos (548 mg, 1.35 mmol), Pd₂(dba)₃ (577 mg, 0.63 mmol) and NaO^(t)Bu(1.9 g, 20.2 mmol) in 1,4-dioxane (18 mL) was stirred at 115° C. for 2 hunder nitrogen. After dilution with EtOAc (200 mL), the mixture waswashed with water and brine. The organic phase was concentrated and theresidue was purified by silica gel column (petroleum ether: EtOAc, 4:1to 2:1) to give the compound tert-butyl4-(4-((4-methoxypyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(1.15 g, yield: 48%) as a gray solid. ESI-MS (M+H)⁺: 375.2.

2. Synthesis of4-methoxy-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

Compound tert-butyl4-(4-((4-methoxypyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(1.14 g, 3.0 mmol) was dissolved in TFA/DCM (10 mL, 1:1). The solutionwas stirred at rt for 1 h and concentrated in vacuo to afford a residue,which was diluted with saturated aqueous Na₂CO₃ solution (50 mL) andextracted with EtOAc (60 mL×3). The combined organic layers were driedover MgSO₄ and concentrated in vacuo to give crude4-methoxy-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (0.9g, yield: 100%) as a light yellow solid, which was used to next stepwithout further purification. ESI-MS (M+H)⁺: 275.1.

3. Synthesis of4-methoxy-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of4-methoxy-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (0.9g, 3.28 mmol), paraformaldehyde (594 mg, 19.8 mmol), NaBH₃CN (623 mg,9.9 mmol) and AcOH (0.1 mL) in MeOH (35 mL) was stirred at rt for 16 h.After concentration, the residue was diluted with DCM (150 mL) andwashed with brine (50 mL×2). The organic phase was concentrated in vacuoto afford a residue which was purified by silica gel column (DCM/MeOH,20:1 with 0.5% NH₃H₂O) to give4-methoxy-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(895 mg, yield: 94%) as a light yellow solid. ESI-MS (M+H)⁺: 545.2. ¹HNMR (400 MHz, CDCl₃) δ: 8.07 (d, J=5.6 Hz, 1H), 7.85 (s, 1H), 7.52 (s,1H), 6.10 (d, J=5.6 Hz, 1H), 4.22-4.07 (m, 1H), 3.92 (s, 3H), 3.09-3.05(m, 1H), 2.41 (s, 3H), 2.36-2.31 (m, 2H), 2.24-2.16 (m, 2H), 2.15-2.03(m, 3H).

4. Synthesis of2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-ol

4-Methoxy-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(890 mg, 3.1 mmol) was dissolved in 40% HBr (aq. 12 mL). The solutionwas stirred at 100° C. for 2 h. The resulting mixture was concentratedin vacuo to give product2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-ol(crude 900 mg, yield: 100%) as a white solid which was used in the nextstep without further purification. ESI-MS (M+H)⁺: 275.1.

5. Synthesis of4-chloro-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

2-((1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-ol (0.9g, 3.1 mmol) was suspended in POCl₃ (10 mL). The mixture was stirred at100° C. for 4 h. After removal of excess POCl₃, the residue was pouredover ice cold water (10 mL). The pH value was adjusted to 7.0-8.0 withsaturated NaHCO₃(aq.). The resulting solution was extracted with EtOAc(50 mL×4). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo to give a crude residue which was purified bysilica gel chromatography (EA/MeOH, 20:1 with 0.5% NH₄OH) to give4-chloro-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(560 mg, yield: 77%) as a light yellow solid. ESI-MS (M+H)⁺: 293.2. ¹HNMR (400 MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.59 (s,1H), 6.75 (d, J=5.2 Hz, 1H), 4.20-4.12 (m, 1H), 3.02-2.99 (m, 2H), 2.34(s, 3H), 2.29-2.22 (m, 2H), 2.16-2.01 (m, 4H).

6. Synthesis of tert-butyl2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

A mixture of4-chloro-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(518 mg, 1.77 mmol), tert-butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(640 mg, 1.84 mmol), Pd(dppf)Cl₂.DCM (120 mg, 0.15 mmol) and K₂CO₃ (488mg, 3.5 mmol) in 1,4-dioxane/H₂O (20 mL, 4:1) was stirred at 115° C. for2 h under nitrogen. After dilution with EtOAc (150 mL), the mixture waswashed with water and dried over Na₂SO₄. The organic phase wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH, 80:1 to 50:1) to give the compound tert-butyl2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate(720 mg, yield: 85%) as a light yellow solid. ESI-MS (M+H)⁺: 478.3. ¹HNMR (400 MHz, CDCl₃) δ: 8.41 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.86 (s,1H), 7.83 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.46-7.28 (m, 2H), 7.06 (d,J=5.2 Hz, 1H), 4.91 (br, 1H), 4.37 (d, J=5.4 Hz, 2H), 4.14-4.09 (m, 1H),2.99-2.97 (m, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.23-2.02 (m, 6H), 1.48(s, 9H).

7. Synthesis of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

tert-Butyl2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate(0.2 g, 0.42 mmol) was dissolved in TFA/DCM (4 mL, 1:1). The solutionwas stirred at rt for 1 h. The mixture was concentrated in vacuo to givecrude product4-(4-(aminomethyl)-3-methylphenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(160 mg, yield: 100%) as a light yellow foam, which was used in the nextstep without further purification. ESI-MS (M+H)⁺: 378.3.

8. Synthesis of5-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide

Synthesis of5-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamidewas similar to that of Example 71. The residue was purified by prep-HPLC(MeCN/H₂O with 0.05% TFA as mobile phase) to afford5-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)isoxazole-3-carboxamide(23 mg, yield: 24%) as a light yellow solid. ESI-MS (M+H)⁺: 529.2. ¹HNMR (400 MHz, CD₃OD) δ: 8.27 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.85 (s,1H), 7.81 (dd, J=8.0, 1.6 Hz, 1H), 7.55 (s, 1H), 7.31 (d, J=8.0 Hz, 1H),7.08 (d, J=5.2 Hz, 1H), 6.39 (s, 1H), 4.52 (s, 2H), 4.11-4.00 (m, 1H),2.93-2.90 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.22-2.15 (m, 2H),2.07-2.04 (m, 2H), 2.02-1.92 (m, 2H), 1.28 (s, 9H).

Example 190:1-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

A mixture of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (252 mg, 0.15mmol),4-(4-(aminomethyl)-3-methylphenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine(58 mg, 0.15 mmol), HATU (69 mg, 0.18 mmol) and DIPEA (60 mg, 0.45 mmol)in DMF (5 mL) was stirred at rt for 2 h. The reaction mixture wasdiluted with water (20 ml) and the mixture was extracted with EtOAc (60mL×2). The combined organic layers were washed with H₂O (40 mL×2), dried(Na₂SO₄), filtered and concentrated in vacuo to afford a residue whichwas purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase)to give1-(tert-butyl)-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (82 mg, yield: 75%). ESI-MS (M+H)⁺: 528.3. ¹H NMR (400MHz, CD₃OD) δ: 8.26 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.87(s, 1H), 7.84 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.30 (d,J=8.0 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 4.48 (s, 2H), 4.05-3.99 (m, 1H),2.90-2.88 (m, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.14-2.12 (m, 2H),2.05-1.90 (m, 4H), 1.49 (s, 9H).

Example 191:3-(tert-butoxy)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of Example 157. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (34 mg, yield: 26%). ESI-MS (M+H)⁺: 504.2. ¹H NMR (400MHz, CD₃OD) δ: 8.41 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.23 (d, J=4.4 Hz,1H), 7.88 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.52 (br, 1H), 7.18 (d, J=5.2Hz, 1H), 4.54-4.49 (m, 1H), 4.49 (s, 2H), 4.11-4.08 (m, 2H), 3.79 (s,3H), 3.73-3.69 (m, 2H), 1.10 (s, 9H).

Example 192:3-(tert-butoxy)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (67 mg, yield: 37%). ESI-MS (M+H)⁺: 532.3. ¹H NMR (400MHz, CD₃OD) δ: 8.42 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 8.21 (d, J=8.0 Hz,1H), 7.95 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.17 (d, J=4.8Hz, 1H), 4.53-4.47 (m, 1H), 4.49 (s, 2H), 4.44-4.37 (m, 1H), 4.11-4.08(m, 2H), 3.73-3.69 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 1.10 (s, 9H).

Example 193:3-(tert-butoxy)-N-(4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (65 mg, yield: 33%). ESI-MS (M+H)⁺: 587.3. ¹H NMR (400MHz, CD₃OD) δ: 8.39 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.21 (d, J=8.0 Hz,1H), 7.96 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=5.2Hz, 1H), 4.53-4.47 (m, 1H), 4.49 (s, 2H), 4.11-4.05 (m, 3H), 3.73-3.69(m, 2H), 2.94-2.91 (m, 2H), 2.24 (s, 3H), 2.19-2.13 (m, 2H), 2.04-1.96(m, 4H), 1.10 (s, 9H).

Example 194:1-(tert-butyl)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

1. The preparation of1-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 1. The crude was purified by silica gelchromatography (petroleum ether:EtOAc=1:1) to give1-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamideas a white solid (215 mg, yield: 78%). ESI-MS (M+H)⁺: 438.1.

2. The preparation of1-(tert-butyl)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 161. The crude was purified prep-HPLC(MeOH/H₂O with 0.05% NH₃.H₂O as mobile phase) to give1-(tert-butyl)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (50 mg, yield: 35%). ESI-MS (M+H)⁺: 554.1. ¹H NMR (400MHz, CDCl₃) δ: 8.47 (d, J=4.8 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J=8.4 Hz,1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.75 (d, J=8.0 Hz, 1H),7.58 (s, 1H), 7.23 (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.30 (t, J=6.0 Hz,1H), 4.92-4.89 (m, 1H), 4.84 (d, J=6.0 Hz, 2H), 3.86-3.82 (m, 2H),3.54-3.50 (m, 2H), 2.45 (s, 3H), 1.60 (s, 9H).

Example 195:1-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 161. The crude was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃H₂O as mobile phase) to give-(tert-butyl)-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (85 mg, yield: 69%). ESI-MS (M+H)⁺: 499.2. ¹H NMR (400MHz, CDCl₃) δ: 8.48 (d, J=4.8 Hz, 1H), 8.41 (s, 1H), 8.14 (d, J=7.2 Hz,1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.78-7.76 (m, 2H), 7.52 (s, 1H), 7.09(d, J=5.2 Hz, 1H), 6.96 (s, 1H), 6.18 (t, J=5.6 Hz, 1H), 4.85 (d, J=6.0Hz, 2H), 3.92 (s, 3H), 1.60 (s, 9H).

Example 196:3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

1. Synthesis ofN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butoxy)azetidine-1-carboxamide

Synthesis ofN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butoxy)azetidine-1-carboxamidewas similar to that of3-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamidein Example 200 except the 3-(tert-butyl)pyrrolidine was substituted with3-(tert-butoxy)azetidine hydrochloride. The crude product was purifiedby prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to giveN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butoxy)azetidine-1-carboxamideas a white solid (1.1 g, yield: 54%). ESI-MS (M+H)⁺: 409.1. ¹H NMR (400MHz, CD₃OD) δ: 7.80 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz,1H), 4.61-4.57 (m, 1H), 4.47 (s, 2H), 3.81-3.77 (m, 2H), 3.32-3.31 (m,2H), 1.19 (s, 9H).

2. Synthesis of3-(tert-butoxy)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide was similar to that of3-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide.The residue was purified by silica gel chromatography column (EtOAc:petroleum ether=1:1) to give3-(tert-butoxy)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (830 mg, yield: 86%). ESI-MS (M+H)⁺: 442.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.70 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=8.0Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 4.64 (d, J=6.4Hz, 2H), 4.54-4.46 (m, 2H), 4.11-4.08 (m, 2H), 3.85-3.83 (m, 2H), 1.17(s, 9H).

3. Synthesis of3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (73 mg, yield: 41%). ESI-MS (M+H)⁺: 518.3. ¹H NMR (400MHz, CD₃OD) δ: 8.41 (s, 1H), 8.36 (d, J=4.8 Hz, 1H), 8.22 (d, J=1.6 Hz,1H), 7.92 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.17 (d, J=5.2Hz, 1H), 4.52-4.49 (m, 1H), 4.51 (s, 2H), 4.11-4.04 (m, 4H), 3.73-3.69(m, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.10 (s, 9H).

Example 197:3-(tert-butoxy)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of Example 161. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (75 mg, yield: 40%). ESI-MS (M+H)⁺: 548.2. ¹H NMR (400MHz, CD₃OD) δ: 8.37 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.22 (d, J=8.4 Hz,1H), 7.94 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.16 (d, J=5.2Hz, 1H), 4.53-4.47 (m, 1H), 4.49 (s, 2H), 4.18 (t, J=5.2 Hz, 2H),4.11-4.07 (m, 2H), 3.73-3.69 (m, 2H), 3.64 (t, J=5.2 Hz, 2H), 3.23 (s,3H), 1.10 (s, 9H).

Example 198:3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidewas similar to that of3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide.After concentration in vacuo, the crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (64 mg, yield: 58%). ESI-MS (M+H)⁺: 534.2. ¹H NMR (400MHz, CD₃OD) δ: 8.39 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.24 (d, J=8.0 Hz,1H), 7.96 (s, 1H), 7.59-7.57 (m, 2H), 7.18 (d, J=4.8 Hz, 1H), 4.54-4.47(m, 1H), 4.50 (s, 2H), 4.12-4.07 (m, 4H), 3.80 (t, J=5.2 Hz, 2H),3.73-3.70 (m, 2H), 1.10 (s, 9H).

Example 199:3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

1. Synthesis of Cert-butyl3-(4-((4-(4-((3-(tert-butoxy)azetidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Synthesis of tert-butyl3-(4-((4-(4-((3-(tert-butoxy)azetidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylatewas similar to that of Example 161. The residue was purified by silicagel chromatography column (EtOAc: petroleum ether=10:1) to givetert-butyl3-(4-((4-(4-((3-(tert-butoxy)azetidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylateas a yellow solid (230 mg, yield: 46%). ESI-MS (M+H)⁺: 645.2.

2. Synthesis of3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide

The synthesis of3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide.A mixture of tert-butyl3-(4-((4-(4-((3-(tert-butoxy)azetidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (230 mg,0.36 mmol) and SOCl₂ (43 mg, 0.36 mmol) in MeOH (10 mL) was stirred atrt for 1 h. After concentration, the crude material (80 mg, 0.16 mmol)was dissolved in MeOH (5 mL), treated with NaBH₃CN (41 mg, 0.64 mmol)and (CHO). (24 mg, 0.64 mmol). The mixture was stirred at rt for 2 h.After concentration in vacuo, the crude product was purified by silicagel chromatography (EtOAc/MeOH=10:1) to give3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamideas a yellow solid (11 mg, yield: 11%). ESI-MS (M+H)⁺: 559.2. ¹H NMR (400MHz, CD₃OD) δ: 8.40 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.23 (d, J=8.0 Hz,1H), 8.06 (s, 1H), 7.63 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.19 (d, J=5.2Hz, 1H), 4.95-4.91 (m, 1H), 4.52-4.48 (m, 1H), 4.49 (s, 2H), 4.11-4.08(m, 2H), 3.89-3.85 (m, 2H), 3.73-3.69 (m, 2H), 3.65-3.60 (m, 2H), 2.46(s, 3H), 1.10 (s, 9H).

Example 200:3-(tert-butyl)-N-(4-(2-(0-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

1. The synthesis ofN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butyl)pyrrolidine-1-carboxamide

To a solution of 4-bromo-2-(trifluoromethyl)phenyl)methanamine (1.46 g,5.8 mmol) in saturated aqueous NaHCO₃/DCM (30 mL, 1:1) was added BTC(690 mg, 2.3 mmol) at 0° C. The mixture was stirred at rt for 1 h. Afterdiluting with DCM (120 mL), the mixture was washed with brine (50 mL).The organic phase was dried (Na₂SO₄), filtered and the solvent wasreduced to about 20 mL. Then DIPEA (2.24 g, 17.4 mmol) and3-(tert-butyl)pyrrolidine (737 mg, 5.8 mmol) was added and the mixturewas stirred at rt for 2 h, diluted with CH₂Cl₂ (100 mL) and washed withbrine (50 mL). The organic phase was concentrated in vacuo and theresidue was purified by prep-HPLC (MeCN/water with 0.05% NH₄OH as mobilephase) to giveN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butyl)pyrrolidine-1-carboxamide(1.5 g, yield: 64%) as yellow solid. ESI-MS (M+H)⁺: 407.1. ¹H NMR (400MHz, CD₃OD): δ: 7.72-7.67 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 4.45-4.42 (m,2H), 3.50-3.48 (m, 1H), 3.41-3.38 (m, 1H), 3.20-3.18 (m, 1H), 3.04-2.99(m, 1H), 2.03-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.66-1.61 (m, 1H), 0.88(s, 9H).

2. The synthesis of3-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

To a mixture ofN-(4-bromo-2-(trifluoromethyl)benzyl)-3-(tert-butyl)pyrrolidine-1-carboxamide(1.5 g, 3.7 mmol) and PinB-BPin (940 mg, 3.7 mmol) in 1,4-dioxane (20mL), KOAc (718 mg, 7.4 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (300 mg, 0.37 mmol) wasadded. The mixture was stirred at 100° C. for 12 h under N₂. Aftercooling to rt, 2,4-dichloropyrimidine (658 mg, 4.44 mmol), K₂CO₃ (766mg, 5.55 mmol) and H₂O (5 mL) were added. The resulting mixture wasstirred at 100° C. for 4 h under N₂. After diluting with EtOAc (200 mL),the mixture was washed with water (50 mL×2). The organic phase was driedand concentrated in vacuo to afford a residue which was purified byprep-HPLC (MeCN/water with 0.05% NH₄OH as mobile phase) to give3-(tert-butyl)-N-(4-(2-chloropyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(750 mg, yield: 50%) as yellow solid. ESI-MS (M+H)⁺: 441.2. ¹H NMR (400MHz, CD₃OD): δ: 8.76-8.74 (m, 1H), 8.50 (d, J=1.2 Hz, 1H), 8.41-8.38 (m,1H), 8.06-8.03 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.63-3.59(m, 1H), 3.53-3.49 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.11 (m, 1H),2.18-2.15 (m, 1H), 1.98-1.93 (m, 1H), 1.77-1.72 (m, 1H), 0.98 (s, 9H).

3. Synthesis of (3S)-tert-butyl3-(4-((4-(4-((3-(tert-butyl)pyrrolidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Synthesis of (3 S)-tert-butyl3-(44(4-(44(3-(tert-butyl)pyrrolidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylatewas similar to that of Example 161. The residue was purified by prep-TLC(PE:EA=1/3) to give (3 S)-tert-butyl3-(44(4-(44(3-(tert-butyl)pyrrolidine-1-carboxamido)methyl)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(280 mg, yield: 63%) as a yellow solid. ESI-MS (M+H)⁺: 657.3.

4. Synthesis of3-(tert-butyl)-N-(4-(2-((1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(4-(2-((1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamidewas similar to that of Example 121. The crude product was purified byprep-HPLC (MeCN/water with 0.05% NH₄OHas mobile phase) to give3-(tert-butyl)-N-(4-(2-((1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(144 mg, yield: 68%) as yellow solid. ESI-MS (M+H)⁺:557.3. ¹H NMR (400MHz, CD₃OD) δ: 8.36 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 8.15 (d, J=8.4 Hz,1H), 7.94 (s, 1H), 7.58-7.56 (m, 2H), 7.11 (d, J=4.8 Hz, 1H), 4.87-4.82(m, 1H), 4.56-4.52 (m, 2H), 3.51-3.49 (m, 2H), 3.40-3.38 (m, 1H),3.31-3.17 (m, 3H), 3.07-2.99 (m, 2H), 2.34-2.25 (m, 1H), 2.18-2.10 (m,1H), 2.05-1.97 (m, 1H), 1.85-1.79 (m, 1H), 1.67-1.56 (m, 1H), 0.85 (s,9H).

5. Synthesis of3-(tert-butyl)-N-(4-(2-((1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

To a solution of3-(tert-butyl)-N-(4-(2-((1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(86 mg, 0.155 mmol) in MeOH (10 mL) was added NaBH₃CN (20 mg, 0.74mmol), (CH₂O)_(n) (47 mg, 1.55 mmol) and AcOH (cat.) in MeOH (10 mL).The mixture was stirred at rt for 16 h. After filtration through aCelite pad, the filtrate was concentrated in vacuo to afford a residuewhich was purified by prep-HPLC (MeCN/water with 0.05% NH₄HCO₃ as mobilephase) to give3-(tert-butyl)-N-(4-(2-((1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide as a yellow solid (53 mg, yield: 40%).ESI-MS (M+H)⁺: 571.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.46 (d, J=5.2 Hz, 1H),8.36 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.78 (d, J=8.0 Hz,1H), 7.55 (s, 1H), 7.06 (d, J=5.2 Hz, 1H), 4.91-4.87 (m, 1H), 4.78-4.76(m, 1H), 4.67-4.65 (m, 2H), 3.54-3.45 (m, 2H), 3.30-3.24 (m, 1H),3.07-2.86 (m, 4H), 2.65-2.59 (m, 1H), 2.53-2.45 (m, 1H), 2.42 (s, 3H),2.29-2.21 (m, 1H), 2.10-2.09 (m, 1H), 1.91-1.85 (m, 1H), 1.73-1.65 (m,1H), 0.92 (s, 9H).

Example 201:3-(tert-butyl)-N-(4-(2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(4-(2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamidewas similar to that of Example 200. The residue was purified by columnchromatography (silica, DCM/MeOH=10:1) to give3-(tert-butyl)-N-(4-(2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide(36 mg, yield: 35%) as a slight yellow solid. ESI-MS (M+H)⁺: 571.3. ¹HNMR (400 MHz, CD₃OD) δ: 8.36-8.33 (m, 2H), 8.19 (d, J=8.4 Hz, 1H), 8.03(s, 1H), 7.60-7.55 (m, 2H), 7.14 (d, J=5.2 Hz, 1H), 4.89-4.85 (m, 1H),4.57-4.50 (m, 2H), 3.52-3.47 (m, 1H), 3.42-3.37 (m, 1H), 3.21-3.15 (m,1H), 3.07-2.93 (m, 4H), 2.74-2.68 (m, 1H), 2.43 (s, 3H), 2.41-2.39 (m,1H), 2.16-2.10 (m, 1H), 2.02-2.01 (m, 1H), 1.87-1.80 (m, 1H), 1.65-1.60(m, 1H), 0.86 (s, 9H).

Example 202:3-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide

Synthesis of3-(tert-butyl)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamidewas similar to Example 198. The crude material was purified by prep-HPLC(MeCN/water with 0.05% NH₄OH as mobile phase) to giveN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(68 mg, yield: 59%) as a yellow solid. ESI-MS (M+H)⁺: 532.3. ¹H NMR (400MHz, CD₃OD) δ: 8.45 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.26 (d, J=7.6 Hz,1H), 8.03 (s, 1H), 7.68-7.66 (m, 2H), 7.21 (d, J=5.6 Hz, 1H), 4.64-4.63(m, 2H), 4.21 (t, J=5.2 Hz, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.62-3.57 (m,1H), 3.52-3.48 (m, 1H), 3.30-3.28 (m, 1H), 3.15-3.10 (m, 1H), 2.13-2.11(m, 1H), 1.93-1.91 (m, 1H), 1.73-1.70 (m, 1H), 0.96 (s, 9H).

Example 203:3-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide

1. The Preparation of tert-butyl2-chloro-4-(2-chloropyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-chloro-4-(2-chloropyrimidin-4-yl)benzylcarbamate was similar to thatof tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. Thecrude was purified by silica gel column (petroleum ether:EtOAc=5:1-3:1)to give tert-butyl 2-chloro-4-(2-chloropyrimidin-4-yl)benzylcarbamate asa white solid (1.3 g, yield: 78%). ESI-MS (M+H)⁺: 354.1. ¹H NMR (400MHz, CD₃OD) δ: 8.73 (d, J=5.2 Hz, 1H), 8.24 (J=1.6 Hz, 1H), 8.12 (dd,J=8.0, 1.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 4.42(s, 2H), 1.26 (s, 9H).

2. The preparation of tert-butyl2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate

Synthesis of tert-butyl2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamatewas similar to that of tert-butyl2-methyl-4-(2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The residue was purified by column chromatography (silica, petroleumether/EtOAc=1:4) to give tert-butyl2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamateas a yellow solid (143 mg, yield: 41%). ESI-MS (M+H)⁺: 415.2.

3. Synthesis of3-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide

To a solution of4-(4-(aminomethyl)-3-chlorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(200 mg, 0.64 mmol) in DMF (5 mL) was added DIPEA (248 mg, 1.92 mmol)and CDI (125 mg, 0.77 mmol). After stirring at rt for 30 min,3-(tert-butyl)pyrrolidine (126 mg, 0.77 mmol) was added to the solution.The resulting solution was stirred for another 2 h, and then purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamideas a yellow solid (120 mg, yield: 53%). ESI-MS (M+H)⁺: 468.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.44 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H),7.88-7.86 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.04 (d, J=5.2Hz, 1H), 6.94 (s, 1H), 4.78-4.76 (m, 1H), 4.57-4.55 (m, 2H), 3.93 (s,3H), 3.59-3.40 (m, 2H), 3.28-3.25 (m, 1H), 3.04 (t, 10.0 Hz, 1H),2.15-2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.67-1.63 (m, 1H), 0.92 (s, 9H).

4. Synthesis of3-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide

An oven-dried pressure tube, which was equipped with a magnetic stirbar, was charged with Pd(OAc)₂ (6 mg, 0.026 mmol), X-phos (25 mg,0.052), K₄[Fe(CN)₆].3H₂O (27 mg, 0.065 mmol), K₂CO₃ (36 mg, 0.26 mmol).The tube was evacuated and backfilled with N₂ for 3 times and then3-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(120 mg, 0.26 mmol) and 1,4-dioxane/water (4:1, 2.0 mL) were added. Thepressure tube was sealed and the mixture was stirred at 100° C. for 10 hand then cooled to rt. The mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue that was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to give3-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamideas a yellow solid (54 mg, yield: 46%). ESI-MS (M+H)⁺: 459.3. ¹H NMR (400MHz, CDCl₃) δ: 8.47 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J=8.0 Hz,1H), 7.86 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.21 (s, 1H),7.03 (d, J=5.2 Hz, 1H), 5.06 (t, J=5.6 Hz, 1H), 4.70-4.54 (m, 2H), 3.93(s, 3H), 3.64-3.39 (m, 2H), 3.35-3.20 (m, 1H), 3.05 (t, J=10.0 Hz, 1H),2.13-1.98 (m, 1H), 1.94-1.83 (m, 1H), 1.73-1.58 (m, 1H), 0.92 (s, 9H).

Example 204:1-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

1. The preparation of1-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 1. The residue was purified by prep-HPLC(CH₃CN/H₂O with 0.05% NH₃.H₂O as mobile phase) to give1-(tert-butyl)-N-(2-chloro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (58 mg, yield: 62%). ESI-MS (M+H)⁺: 465.2. ¹H NMR (400MHz, CD₃OD) δ: 8.61 (t, J=5.6 Hz, 1H), 8.31-8.29 (m, 1H), 8.18 (s, 1H),8.07 (s, 1H), 7.91-7.88 (m, 2H), 7.83 (s, 1H), 7.51 (s, 1H), 7.41 (d,J=8.0 Hz, 1H), 7.08-7.06 (m, 1H), 4.56 (s, 2H), 3.77 (s, 3H), 1.49 (s,9H).

2. The preparation of1-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of Example 203. The crude product was purified byprep-TLC (petroleum ether: EtOAc=1/3) to give1-(tert-butyl)-N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamideas a yellow solid (6 mg, yield: 4%). ESI-MS (M+H)⁺: 456.2. ¹H NMR (400MHz, CDCl₃) δ: 8.47 (d, J=4.8 Hz, 1H), 8.31 (d, J=1.2 Hz, 1H), 8.18 (dd,J=6.8, 1.2 Hz, 1H), 8.05 (s, 1H), 7.85-7.84 (m, 1H), 7.72 (d, J=8.4 Hz,1H), 7.52 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=5.6 Hz, 1H), 6.59 (br, 1H),4.82 (d, J=6.4 Hz, 2H), 3.92 (s, 3H), 1.60 (s, 9H).

Example 205:3-isopropoxy-N-(2-methyl-4-(2-((1-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

1. Synthesis ofN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

Synthesis ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamidewas similar to that ofN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide.The crude was purified through silica gel column chromatography(MeOH/DCM=1/30) to giveN-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(130 mg, yield: 77%) as yellow oil. ESI-MS (M+H)⁺: 375.0.

2. Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude product was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OHas mobile phase) to give3-isopropoxy-N-(2-methyl-4-(2-((1-(2-methyl-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a yellow solid (112 mg, yield: 54%). ESI-MS (M+H)⁺: 521.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H),7.94 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.23 (d,J=5.2 Hz, 1H), 4.46-4.40 (m, 1H), 4.39 (s, 2H), 4.19-4.16 (m, 2H),3.82-3.79 (m, 2H), 3.69-3.64 (m, 1H), 2.71 (s, 3H), 2.43 (s, 3H), 1.83(s, 6H), 1.17 (d, J=5.6 Hz, 6H).

Example 206:3-isopropoxy-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The residue was purified by silica gel column chromatography (EtOAc:petroleum ether=2:1) to give3-isopropoxy-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamideas a yellow solid (85 mg, yield: 25%). ESI-MS (M+H)⁺: 480.2. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.85-7.83 (m, 2H),7.56 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 4.33-4.30(m, 1H), 4.28 (s, 2H), 4.19 (t, J=5.2 Hz, 2H), 4.09-4.05 (m, 2H),3.72-3.68 (m, 2H), 3.65 (t, J=5.2 Hz, 2H), 3.59-3.53 (m, 1H), 3.25 (s,3H), 2.33 (s, 3H), 1.05 (d, J=6.4 Hz, 6H).

Example 207:3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamidewas similar to that ofN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamideexcept the 3-isopropoxyazetidine was substituted for the3-(tert-butoxy)azetidine. The crude was purified by prep-HPLC (MeCN/H₂Owith 0.05% NH₄OH as mobile phase) to give3-(tert-butoxy)-N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamideas a yellow solid (80 mg, yield: 54%). ESI-MS (M+H)⁺: 480.3. ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.95-7.93 (m, 2H),7.68 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 4.61-4.55(m, 1H), 4.38 (s, 2H), 4.23 (t, J=5.2 Hz, 2H), 4.19-4.15 (m, 2H), 3.91(t, J=5.2 Hz, 2H), 3.80-3.77 (m, 2H), 2.43 (s, 3H), 1.20 (s, 9H).

Example 208:3-(tert-butoxy)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamide.The crude product was purified by silica gel column chromatography(MeOH/DCM=1/8) to give3-(tert-butoxy)-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a yellow solid (95 mg, yield: 40%). ESI-MS (M+H)⁺: 505.3. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.83-7.82 (m, 2H),7.63 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 4.93-4.85(m, 1H), 4.50-4.44 (m, 1H), 4.27 (s, 2H), 4.07-4.03 (m, 2H), 3.81-3.77(m, 2H), 3.69-3.66 (m, 2H), 3.54-3.50 (m, 2H), 2.40 (s, 3H), 2.31 (s,3H), 1.09 (s, 9H).

Example 209:3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamidewas similar to that of3-(tert-butyl)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxamide.The crude product was purified by silica gel column chromatography(EtOAc: petroleum ether=4/1) to give3-(tert-butoxy)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamideasas a yellow solid (100 mg, yield: 57%). ESI-MS (M+H)⁺: 464.2. ¹H NMR(400 MHz, CD₃OD) δ: 8.39 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.94-7.92 (m,2H), 7.66 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H),4.61-4.55 (m, 1H), 4.38 (s, 2H), 4.21-4.15 (m, 4H), 3.80-3.77 (m, 2H),2.43 (s, 3H), 1.49 (t, J=7.2 Hz, 3H), 1.20 (s, 9H).

Example 210:N-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

1. Synthesis ofN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

Synthesis ofN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The crude product was purified by silica gel column chromatography(EA/PE=3/1) to giveN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamideas a yellow solid (70 mg, yield: 53%). ESI-MS (M+H)⁺: 580.4.

2. Synthesis ofN-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

A mixture ofN-(4-(2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(70 mg, 0.12 m mol) in 3 N HCl in methanol (4 mL) was stirred at rt for1 h. The solvent was removed in vacuo and the residue was purified byprep-HPLC (MeCN/H₂O with 0.05% NH₃H₂O as mobile phase) to giveN-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamideas a yellow solid (32 mg, yield: 57%). ESI-MS (M+H)⁺: 466.2. ¹H NMR (400MHz, CDCl₃) δ: 8.36 (d, J=4.8 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.77(s, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.02 (d,J=5.6 Hz, 1H), 4.54 (t, J=5.6 Hz, 1H), 4.40 (d, J=5.2 Hz, 2H), 4.37-4.31(m, 1H), 4.21 (t, J=4.8 Hz, 2H), 4.14-4.12 (m, 2H), 3.98 (t, J=5.2 Hz,2H), 3.88-3.85 (m, 2H), 3.63-3.57 (m, 1H), 2.37 (s, 3H), 1.50 (d, J=5.6Hz, 6H).

Example 211:3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of tert-butyl2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzylcarbamate.The residue was purified by silica gel column chromatography(EtOAc/petroleum ether=2:1) to give3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas yellow solid (48 mg, yield: 30%). ESI-MS (M+H)⁺: 491.2. ¹H NMR (400MHz, CD₃OD) δ: 8.29 (d, J=5.6 Hz, 1H), 8.09 (s, 1H), 7.84-7.83 (m, 2H),7.63 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 4.93-4.85(m, 1H), 4.35-4.30 (m, 1H), 4.28 (s, 2H), 4.09-4.05 (m, 2H), 3.79-3.68(m, 4H), 3.59-3.48 (m, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 1.05 (d, J=6.4Hz, 6H).

Example 212:3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

1. Synthesis of tert-butyl4-(4-((4-(4-((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of tert-butyl4-(4-((4-(4-((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas similar to that of3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide.The crude product was purified through silica gel column chromatography(MeOH/CH₂Cl₂=1/20) to give tert-butyl4-(4-((4-(4-((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a yellow oil (105 mg, yield: 32%). ESI-MS (M+H)⁺: 605.3. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.82(d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.07 (d, J=5.2Hz, 1H), 6.89 (s, 1H), 4.45 (d, J=5.6 Hz, 2H), 4.38-4.33 (m, 1H),4.30-4.22 (m, 3H), 4.16-4.11 (m, 2H), 3.88-3.85 (m, 2H), 3.64-3.58 (m,1H), 2.94-2.86 (m, 2H), 2.42 (s, 3H), 2.18-2.16 (m, 2H), 2.00-1.91 (m,2H), 1.48 (s, 9H), 1.16 (d, J=6.4 Hz, 6H).

2. Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of3-(tert-butoxy)-N-(4-(2-((1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine-1-carboxamidein Example 199. The crude product was purified through prep-TLC (silicagel, MeOH/CH₂Cl₂=1/9) to give3-isopropoxy-N-(2-methyl-4-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamideas a white solid (30 mg, yield: 33%). ESI-MS (M+H)⁺: 519.2. ¹H NMR (400MHz, CD₃OD) δ: 8.32 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 7.86(d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.14 (d, J=5.6Hz, 1H), 4.38-4.34 (m, 1H), 4.31 (s, 2H), 4.26-4.21 (m, 1H), 4.12-4.08(m, 2H), 3.75-3.71 (m, 2H), 3.62-3.56 (m, 1H), 3.21-3.18 (m, 2H),2.63-2.58 (m, 2H), 2.51 (s, 3H), 2.36 (s, 3H), 2.20-2.06 (m, 4H), 1.09(d, J=6.4 Hz, 6H).

Example 213:trans-N-(4-(2-((1-((3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

1. Synthesis of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

To the solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate(2.0 g, 9.2 mmol, 1.0 equiv) in MeOH (15 mL), NaBH₄(525 mg, 13.8 mmol,1.5 equiv) was slowly added at 0° C. The reaction mixture was stirred atrt for 4 h. After diluting with water (80 mL), the mixture was extractedwith ethyl acetate (100 mL×2). The combined organic layers were washedwith brine, dried, concentrated and purified by silica gel columnchromatography (petroleum ether:EtOAc=5:1) to give tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate (1.8 g, yield: 90%) as ayellow solid. ESI-MS (M+H-56)⁺: 164.1.

2. Synthesis of tert-butyl3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of 4-nitro-1H-pyrazole (1.13 g, 10 mmol), tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate (2.19 g, 10 mmol) and PPh₃(2.88 g, 11 mmol) in THF (25 mL) was added DIAD (2.22 g, 11 mmol) undernitrogen. The mixture was stirred at rt for 2 h. The mixture was dilutedwith EtOAc (150 mL) and washed with water (50 mL×2). The organic phasewas concentrated in vacuo and the residue was purified by columnchromatography (silica gel, petroleum ether:EtOAc=3:1) to give the titleproduct tert-butyl3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.3 g,yield: 91%) as a yellow solid. ESI-MS (M+H)⁺: 315.1. ¹H NMR (400 MHz,CDCl₃) δ: 8.70 (s, 1H), 8.19 (s, 1H), 4.91-4.88 (m, 2H), 4.72-4.61 (m,1H), 4.48-4.47 (m, 2H), 4.11-4.10 (m, 1H), 2.10-2.09 (m, 2H), 1.49 (s,9H).

3. Synthesis of tert-butyl3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of tert-butyl3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate was similarto that of (R)-tert-butyl3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate in Example 121.After the catalyst was removed, the solvent was removed and the crudeproduct (410 mg, yield: 91%) was used to next step without furtherpurification. ESI-MS (M+H)⁺: 285.2.

4. Synthesis ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

Synthesis ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamidewas similar to that of Example 205. The crude was purified throughprep-HPLC (NH₃H₂O(0.05%)/MeCN as a mobile phase) to givetrans-tert-butyl3-fluoro-4-(4-((4-(4-((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(88 mg, yield: 26%) as a yellow solid. ESI-MS (M+H)⁺:623.3.

5. Synthesis of trans-tert-butyl3-fluoro-4-(4-((4-(4((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Synthesis of trans-tert-butyl3-fluoro-4-(4-((4-(4-((3-isopropoxyazetidine-1-carboxamido)methyl)-3-methylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas similar to that oftrans-N-(4-(2-((1-(3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide.The crude product was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OHas mobile phase) to givetrans-N-(4-(2-((1-(3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(72 mg, yield: 97%) as a yellow solid. ESI-MS (M+H)⁺:523.3.

6. Synthesis oftrans-N-(4-(2-((1-((-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

Synthesis oftrans-N-(4-(2-((1-((-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamidewas similar to that of Example 199. The crude product was purified byprep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH as mobile phase) to givetrans-N-(4-(2-((1-(-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(28 mg, yield: 38%) as yellow solid. ESI-MS (M+H)⁺:537.3. ¹H NMR (400MHz, CD₃OD) δ: 8.28 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.81-7.79 (m, 2H),7.60 (s, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 4.71-4.65(m, 1H), 4.31-4.26 (m, 3H), 4.13-4.03 (m, 3H), 3.71-3.67 (m, 2H),3.56-3.50 (m, 1H), 3.18-3.14 (m, 1H), 2.82-2.80 (m, 1H), 2.29 (s, 3H),2.27 (s, 3H), 2.15-2.00 (m, 4H), 1.04 (d, J=6.4 Hz, 6H).

Example 214:3-isopropoxy-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

Synthesis of3-isopropoxy-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamidewas similar to that of3-isopropoxy-N-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide.The residue was purified by prep-HPLC (MeCN/water with 0.05% NH₄OH asmobile phase) to give3-isopropoxy-N-(2-methyl-4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide(63 mg, yield: 39%) as a yellow solid. ESI-MS (M+H)⁺: 506.2. ¹H NMR (400MHz, CDCl₃) δ: 8.42 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.81(d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.36 (d, J=8.0 Hz, 1H),7.06 (d, J=5.2 Hz, 1H), 4.50-4.47 (m, 1H), 4.43 (d, J=5.2 Hz, 2H),4.38-4.29 (m, 2H), 4.16-4.10 (m, 4H), 3.89-3.85 (m, 2H), 3.64-3.52 (m,3H), 2.39 (s, 3H), 2.15-2.04 (m, 4H), 1.15 (d, J=6.4 Hz, 6H).

Example 215:N-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide

To a solution ofN-(4-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamide(220 mg, 0.60 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate(132 mg, 0.72 m mol) in dry 1,4-dioxane (8 mL) was added Pd₂(dba)₃ (55mg, 0.06 mmol), S-phos (49 mg, 0.12 mmol) and Cs₂CO₃ (390 mg, 1.2 mmol).The mixture was stirred at 120° C. for 4 h under N₂. After cooling tort, the mixture was diluted with EtOAc (150 mL) and washed with water(60 mL×2). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was dissolved in 3 N HCl in MeOH (10mL) and the resulting mixture was stirred at rt for 1 h. Afterconcentration in vacuo, the residue was purified by prep-HPLC (CH₃CN/H₂Owith 0.05% NH₄OH as mobile phase) to giveN-(4-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-3-isopropoxyazetidine-1-carboxamideas a white solid (88 mg, yield: 35%). ESI-MS (M+H)⁺: 544.2. ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=4.8 Hz, 1H), 8.05 (s, 1H), 7.91-7.90 (m, 2H),7.75 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 4.42-4.36(m, 3H), 4.18-4.14 (m, 2H), 3.81-3.78 (m, 2H), 3.67-3.61 (m, 1H), 2.41(s, 3H), 1.14 (d, J=6.0 Hz, 6H).

Example 216:3-(tert-butoxy)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide

1. Synthesis ofN-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine

To a solution of 2-chloro-4-methoxypyrimidine (1.44 g, 10 mmol) in1,4-dioxane (25 mL) were added 1,5-dimethyl-1H-pyrazol-4-amine (1.21 g,11 mmol), Pd₂(dba)₃ (915 mg, 1.0 mmol), S-Phos (822 mg, 2.0 mmol) andCs₂CO₃ (6.5 g, 20 mmol). The mixture was stirred at 100° C. for 3 h.After cooling to rt, the mixture was filtered through a Celite pad. Thefiltrate was concentrated in vacuo and the crude was purified by silicagel column chromatography (petroleum ether: EtOAc=2/1) to giveN-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine as a yellowsolid (1.75 g, yield: 80%). ESI-MS (M+H)⁺: 220.1.

2. Synthesis of 2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ol

A solution ofN-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine (1.0 g, 4.57mmol) in HBr (15 mL) was stirred at 100° C. for 2 h. The mixture wasconcentrated and the crude product (930 mg) was used to next stepwithout further purification. ESI-MS (M+H)⁺: 206.1

3. Synthesis of4-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

A solution of 2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ol (930mg, 4.51 mmol) in POCl₃ (20 mL) was stirred at 100° C. for 16 h. Aftercooling to rt, the mixture was poured onto ice-water and adjusted topH=8 with Na₂CO₃ (sat). The mixture was extracted with ethyl acetate(200 mL×2). The combined organic layers were washed with brine, dried,concentrated in vacuo to afford a residue which was purified by silicagel column chromatography (petroleum ether:EtOAc=1:1) to give4-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (680 mg,yield: 67%) as a yellow solid. ESI-MS (M+H)⁺: 224.1.

4. Synthesis of3-(tert-butoxy)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide

A mixture ofN-(4-bromo-2-methylbenzyl)-3-(tert-butoxy)azetidine-1-carboxamide (193mg, 0.5 mmol), bis(pinacolato)diboron (134 mg, 0.55 mmol), KOAc (98 mg,1.0 mmol) and Pd(dppf)Cl₂.DCM (41 mg, 0.05 mmol) in 5 mL dry 1,4-dioxanewas stirred at 100° C. for 2 h under nitrogen. After cooling to rt,4-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (134 mg, 0.6mmol), K₂CO₃ (138 mg, 1.0 mmol) and H₂O (2 mL) were added. The resultingmixture was stirred at 100° C. for another 2 h. The mixture was dilutewith EtOAc (200 mL), washed with water (80 mL×2), dried with Na₂SO₄ andconcentrated. The residue was purified by prep-HPLC (MeCN/H₂O with 0.05%NH₄OH as mobile phase from 5% to 95%) to give3-(tert-butoxy)-N-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)azetidine-1-carboxamide(43 mg, yield: 22%) as yellow solid. ESI-MS (M+H)⁺:464.3. ¹H NMR (400MHz, CD₃OD): 8.26 (d, J=5.2 Hz, 1H), 7.88-7.86 (m, 2H), 7.60 (s, 1H),7.34 (d, J=8.0 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 4.55-4.53 (m, 1H), 4.35(s, 2H), 4.16-4.12 (m, 2H), 3.79 (s, 3H), 3.78-3.75 (m, 2H), 2.38 (s,3H), 2.21 (s, 3H), 1.18 (s, 9H).

Example 217:3-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide

A solution of4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (165 mg, 0.50 mmol), CDI (123 mg, 0.75 mmol) and TEA (151mg, 1.5 mmol) in DMF (4 mL) was stirred at rt for 1 h, then3-(tert-butyl)pyrrolidine (65 mg, 0.50 mmol) was added. The resultingsolution was stirred for another 16 h. After diluting with water (15mL), the mixture was extracted with CH₂Cl₂ (40 mL×3). The combinedorganic phases were washed with brine, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by prep-HPLC (MeCN/water with 0.05%ammonia as mobile phase) to give3-(tert-butyl)-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(89 mg, yield: 41%) as a yellow solid. ESI-MS (M+H)⁺: 448.1. ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.94-7.92 (m, 2H),7.65 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.19 (d, J=5.2 Hz, 1H), 4.42 (ABq,J=23.2, 16.0 Hz, 2H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.50-3.46 (m,1H), 3.28-3.26 (m, 1H), 3.12-3.10 (m, 1H), 2.44 (s, 3H), 2.12-2.08 (m,1H), 1.97-1.90 (m, 1H), 1.78-1.67 (m, 1H), 0.97 (s, 9H).

Example 218:1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

Synthesis of1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamidewas similar to that of2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide.The residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% TFA asmobile phase) to give1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamideas a white solid (10 mg, yield: 30%). ESI-MS (M+H)⁺: 540.2. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.54 (d, J=2.51 Hz, 11H) 2.42 (s, 2H) 2.86-2.89 (m,2H) 2.95-3.04 (m, 1H) 3.15-3.25 (m, 1H) 3.52-3.57 (m, 1H) 3.80-3.88 (m,1H) 4.45-4.49 (m, 1H) 7.39-7.42 (m, 1H) 7.55-7.59 (m, 1H) 7.77-7.81 (m,1H) 7.81-7.83 (m, 1H) 7.83-7.86 (m, 1H) 7.93 (d, J=0.50 Hz, 1H)8.04-8.09 (m, 1H) 8.12-8.16 (m, 1H) 8.25 (s, 1H) 8.33 (d, J=0.75 Hz, 1H)8.48-8.53 (m, 1H) 8.76-8.80 (m, 1H).

Example 219:1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-3-carboxamide

Synthesis1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-3-carboxamidewas similar to that of2-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)thiazole-5-carboxamide.The residue was purified by prep-HPLC (CH₃CN/H₂O with 0.05% TFA asmobile phase) to give1-(tert-butyl)-N-(2-methyl-4-(6-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-3-carboxamideas a white solid (56 mg, yield: 56%). ESI-MS (M+H)⁺: 540.2 ¹H NMR (400MHz, DMSO-d₆) δ: ppm 1.54 (d, J=2.51 Hz, 11H) 2.42 (s, 2H) 2.86-2.89 (m,2H) 2.95-3.04 (m, 1H) 3.15-3.25 (m, 1H) 3.52-3.57 (m, 1H) 3.80-3.88 (m,1H) 4.45-4.49 (m, 1H) 7.39-7.42 (m, 1H) 7.55-7.59 (m, 1H) 7.77-7.79 (m,1H) 7.83-7.86 (m, 1H) 7.93 (d, J=0.50 Hz, 1H) 8.04-8.09 (m, 1H)8.12-8.16 (m, 1H) 8.25 (s, 1H) 8.33 (d, J=0.75 Hz, 1H) 8.48-8.53 (m, 1H)8.76-8.80 (m, 1H).

Example 220:(R)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideand(S)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

3-isopropoxy-azetidine-1-carboxylic acid(2-{2-[1-(2-methoxy-ethyl)-1H-pyrazol-4-ylamino]-pyrimidin-4-yl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide(20 mg, 0.04 mmol) was separated by chiral column. The following SFCmethod was used: OZ—H (2×25 cm) 40% methanol (0.1% DEA)/CO₂, 100 bar; 50mL/min, 220 nm.; inj vol.: 1 mL, 2 mg/mL methanol. Two isomers wereobtained: 9 mg of(R)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.21 min.; MH+520.2; ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=3.51 Hz, 1H), 8.08 (s, 1H), 7.83-7.99 (m, 2H),7.58-7.76 (m, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.19 (d, J=5.27 Hz, 1H),6.86 (d, J=8.03 Hz, 1H), 4.98-5.10 (m, 1H), 4.39-4.51 (m, 1H), 4.15-4.35(m, 4H), 3.75 (t, J=5.15 Hz, 5H), 3.35 (s, 3H), 2.89-3.10 (m, 2H),1.80-2.09 (m, 3H), 1.57-1.75 (m, 1H), 1.31-1.49 (m, 2H), 1.11-1.23 (m,6H); and 8 mg of(S)-3-isopropoxy-N-(2-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.21 min.; MH+520.2; ¹H NMR (400MHz, CD₃OD) δ: 8.38 (d, J=4.52 Hz, 1H), 8.08 (s, 1H), 7.84-7.99 (m, 2H),7.58-7.76 (m, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.19 (d, J=5.27 Hz, 1H),6.86 (d, J=8.03 Hz, 1H), 5.04 (d, J=10.04 Hz, 1H), 4.39-4.51 (m, 1H),4.14-4.34 (m, 4H), 3.60-3.94 (m, 5H), 3.35 (s, 3H), 2.90-3.09 (m, 2H),1.84-2.06 (m, 3H), 1.59-1.75 (m, 1H), 1.31-1.50 (m, 2H), 1.13-1.23 (m,6H).

Example 221:(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamideand(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide

3-tert-Butoxy-azetidine-1-carboxylic acid(2-{2-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylamino]-pyrimidin-4-yl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide(40 mg, 0.08 mmol) was separated by chiral column. The following SFCmethod was used: IA (2×15 cm), 35% methanol (0.1% DEA)/CO₂, 100 bar; 60mL/min, 220 nm.; inj vol.: 1 mL, 4 mg/mL methanol. Two isomers wereobtained: 11 mg of(R)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.16 min.; MH+520.2; ¹H NMR (400MHz, CD₃OD) δ: 8.37 (d, J=4.52 Hz, 1H), 8.07 (s, 1H), 7.84-7.99 (m, 2H),7.59-7.75 (m, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.19 (d, J=5.02 Hz, 1H),5.04 (d, J=10.04 Hz, 1H), 4.53-4.67 (m, 1H), 4.13-4.29 (m, 4H),3.73-3.98 (m, 4H), 2.87-3.09 (m, 2H), 1.79-2.06 (m, 4H), 1.55-1.75 (m,1H), 1.31-1.47 (m, 2H), 1.22 (s, 9H); and 9 mg of(S)-3-(tert-butoxy)-N-(2-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)azetidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.16 min.; MH+520.2; ¹H NMR (400MHz, CD₃OD) δ: 8.37 (d, J=4.52 Hz, 1H), 8.07 (s, 1H), 7.84-7.99 (m, 2H),7.60-7.76 (m, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.19 (d, J=5.27 Hz, 1H),5.04 (d, J=10.29 Hz, 1H), 4.55-4.66 (m, 1H), 4.12-4.32 (m, 4H),3.74-3.98 (m, 4H), 2.89-3.09 (m, 2H), 1.78-2.06 (m, 4H), 1.55-1.75 (m,1H), 1.30-1.49 (m, 2H), 1.22 (s, 9H).

Example 222:1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

1. Synthesis of (4-bromo-2-methylphenyl)methanamine hydrochloride

To a solution of 4-bromo-2-methylbenzonitrile (3.0 g, 15 mmol) inanhydrous THF (20 mL) under nitrogen at 0° C. was added 1.0 M solutionof borane in THF (46 mL). The reaction mixture was stirred at 0° C. for1 h, and heated at 80° C. overnight. The reaction mixture was cooled to0° C. and slowly quenched with MeOH, concentrated in vacuo. The crudeproduct was treated with EtOAc (20 mL) and 4 M of HCl in 1,4-dioxane(8.0 mL, 32 mmol) for 5 min. The solid was filtered, rinsed with diethylether, dried to give the title compound as a white powder (3.24 g,yield: 100%). LCMS: RT 0.75 min.; MH+200.0. ¹H NMR (300 MHz, DMSO-d₆) δ:8.28 (br. s., 2H), 7.42-7.54 (m, 2H), 7.34 (d, J=7.93 Hz, 1H), 3.99 (d,J=4.15 Hz, 2H), 2.35 (s, 3H).

2. Synthesis ofN-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide

To a solution of 1-tert-Butyl-1H-pyrazole-4-carboxylic acid (1.4 g, 8.4mmol) in DMF (20 mL) was added HATU (3.5 g, 9.2 mmol) and DIEA (4.4 mL,25 mmol). The mixture was stirred at rt for 5 min, followed by theaddition of (4-bromo-2-methylphenyl)methanamine hydrochloride (2.0 g,8.4 mmol). The reation was stirred at rt overnight, diluted with EtOAc,washed with water, and the organic phase was then dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product, which was purified bysilica gel chromatography (EtOAc/heptane gradient) to give the titlecompound as a white powder (2.21 g, yield: 92%). LCMS: RT 1.59 min.;MH+350.0; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.41 (t, J=5.65 Hz, 1H), 8.29 (s,1H), 7.89 (s, 1H), 7.28-7.44 (m, 2H), 7.16 (d, J=8.03 Hz, 1H), 4.34 (d,J=5.52 Hz, 2H), 2.30 (s, 3H), 1.52 (s, 9H).

3. Synthesis of1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)-1H-pyrazole-4-carboxamide

To a degassed solution ofN-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide (2.0g, 5.7 mmol) and KOAc (1.68 g, 17.1 mmol) in 1,4-dioxane (50 mL) wasadded Pd(dppf)Cl₂.CH₂Cl₂ (1:1) (0.23 g, 0.28 mmol) andbis(pinacolato)diboron (1.6 g, 6.3 mmol). The solution was heated toreflux for 2 h, cooled to rt, diluted with EtOAc and filtered. Thefiltrate was concentrated in vacuo, and purified by silica gelchromatography (EtOAc/Heptane gradient) to give the title compound as anoff white powder (2.1 g, yield: 95%). LCMS: RT 1.71 min.; MH+398.3; ¹HNMR (400 MHz, DMSO-d₆) δ: 8.41 (t, J=5.65 Hz, 1H), 8.30 (s, 1H), 7.90(s, 1H), 7.42-7.50 (m, 2H), 7.23 (d, J=7.53 Hz, 1H), 4.40 (d, J=5.77 Hz,2H), 2.30 (s, 3H), 1.45-1.59 (m, 9H), 1.28 (s, 12H).

4. Synthesis of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

A mixture of1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole-4-carboxamide(1.33 g, 3.35 mmol) and 4,6-dichloropyrimidine (0.60 g, 4.0 mmol) in1,4-dioxane (20.0 mL) was degassed with nitrogen, follow by the additionof. [Pd(dppf)Cl₂.CH₂Cl₂ (273 mg, 0.33 mmol) and a solution of K₂CO₃(0.92 g, 6.7 mmol) in water (1.0 mL). The reaction was heated at 110° C.for 2 h, cooled down to rt, diluted with EtOAc and washed with water.The organic layer was dried (Na₂SO₄), concentrated in vacuo, andpurified by silica gel chromatography (EtOAc/heptane) to give the titlecompound as a white powder (0.74 g, yield: 55%). LCMS: RT 1.52 min.;MH+384.0; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.07 (d, J=0.50 Hz, 1H), 8.50 (t,J=5.65 Hz, 1H), 8.31 (d, J=13.05 Hz, 2H), 8.00-8.15 (m, 2H), 7.92 (s,1H), 7.39 (d, J=8.03 Hz, 1H), 4.46 (d, J=5.77 Hz, 2H), 2.41 (s, 3H),1.53 (s, 9H).

5. Synthesis of1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

A mixture of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(350.0 mg, 0.912 mmol) and2-amino-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acidtert-butyl ester (282.4 mg, 1.18 mmol) in PhCH₃ (10.0 mL) was degassed.To the solution was added2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (75 mg, 0.18 mmol) andPd₂(dba)₃ (83 mg, 0.09 mmol) and sodium tert-butoxide (263 mg, 2.7mmol). The mixture was degassed, and then heated in a microwave to 100°C. for 1 h. The reaction was cooled to rt, diluted with EtOAc, washedwith water, and the organic phase was separated, dried (Na₂SO₄),concentrated in vacuo, and purified by reverse phase chromatography(C₁₈-gradient 10 to 90% ACN/water with 0.1% TFA). The product wasextracted with EtOAc to give an oil (LCMS: RT 1.29 min.; MH+586.3) whichwas then dissolved in 1,4-dioxane (2.0 mL, 26 mmol) and treated with 4 Msolution of HCl in 1,4-dioxane (2.0 mL, 8.0 mmol). The reaction wasstirred overnight and concentrated in vacuo to afford a residue whichwas then precipitated from dietheyl ether to afford a solid, which wasused without further purification (320 mg, yield: 67% as HCl salt).LCMS: RT 0.85 min.; MH+486.3; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.00 (br.s., 2H), 8.85 (s, 1H), 8.60 (t, J=5.65 Hz, 1H), 8.36 (s, 1H), 7.93 (s,1H), 7.68-7.84 (m, 2H), 7.44 (d, J=8.03 Hz, 1H), 4.36-4.53 (m, 4H), 4.30(t, J=5.52 Hz, 2H), 3.66 (br. s., 2H), 2.42 (s, 3H), 1.53 (s, 9H).

Example 223:1-(tert-butyl)-N-(4-(6-((5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

To a solution of1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-c]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(100 mg, 0.20 mmol), triethylamine (0.03 mL, 0.20 mmol), and 5.0 M ofacetaldehyde in water (2 mL, 9 mmol) was added sodiumtriacetoxyborohydride (87 mg, 0.41 mmol) and heated heated in amicrowave at 90° C. for 20 min. The reaction mixture was then dilutedwith EtOAc, washed with brine, dried and concentrated in vacuo to afforda residue which was purified by silica gel chromatography (DCM+10% to100% 2M NH₃/MeOH) to give the title compound as a white powder (86 mg,yield: 84%). LCMS: RT 0.82 min.; MH+514.2; ¹H NMR (400 MHz, CD₃OD) δ:8.59 (d, J=0.75 Hz, 1H), 8.27 (s, 1H), 7.96 (s, 1H), 7.69-7.83 (m, 2H),7.52 (br. s., 1H), 7.40 (d, J=8.03 Hz, 1H), 6.25 (br. s., 1H), 4.59 (s,2H), 4.12 (t, J=5.52 Hz, 2H), 3.72 (s, 2H), 3.01 (t, J=5.65 Hz, 2H),2.67 (q, J=7.19 Hz, 2H), 2.45 (s, 3H), 1.60 (s, 9H), 1.20 (t, J=7.28 Hz,3H).

Example 224:1-(tert-butyl)-N-(4-(64(5-(2-hydroxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

To a solution of1-(tert-butyl)-N-(2-methyl-4-(6-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(240 mg, 0.49 mmol) and Et₃N (69 uL, 0.49 mmol) in 1,2-dichloroethane(4.0 mL), was added AcOH (28 uL, 0.49 mmol), [1,4]dioxane-2,5-diol (89mg, 0.74 mmol) and sodium triacetoxyborohydride (200 mg, 0.99 mmol). Thereaction mixture was stirred at rt for 1 h, extracted with EtOAc, andwashed with aqueous NaHCO₃ and brine. The organic layer was separated,dried (MgSO₄), filtered and concentrated in vacuo to afford a residuewhich was purified by reverse phase chromatography (CH₃CN/H₂O with 0.05%TFA as mobile phase) to give the title compound as a white powder (178mg, yield: 51% as TFA salt). LCMS: RT 0.85 min.; MH+530.3; ¹H NMR (400MHz, DMSO-d₆) δ: 10.41 (br. s., 1H), 8.73 (d, J=1.00 Hz, 1H), 8.51 (t,J=5.77 Hz, 1H), 8.32 (d, J=0.75 Hz, 1H), 7.92 (d, J=0.50 Hz, 1H),7.71-7.87 (m, 1H), 7.63 (br. s., 1H), 7.39 (d, J=8.03 Hz, 1H), 6.52 (br.s., 1H), 4.17-4.76 (m, 6H), 3.65-3.97 (m, 4H), 3.38 (br. s., 2H), 2.41(s, 3H), 1.53 (s, 9H).

Example 225:1-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

A solution of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(350 mg, 0.91 mmol) and tert-butyl2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate(406 mg, 1.2 mmol) in PhCH₃ (10 mL, 94 mmol) was degassed for 5 min,followed by the addition of2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (75 mg, 0.18 mmol) andtris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.09 mmol) and sodiumtert-butoxide (263 mg, 2.7 mmol), and degassed for another 5 min. Themixture was heated in a microwave at 100° C. for 1 h, cooled to rt anddiluted with EtOAc. The organic phase was washed with water, separated,dried (Na₂SO₄), and concentrated in vacuo to afford a residue. The crudematerial was purified by prep HPLC (C₁₈-gradient 10 to 90% ACN/waterwith 0.1% TFA), followed by extraction with EtOAc and concentrating invacuo to give a light yellow oil (LCMS: RT 1.27 min.; MH+600.3). The Bocprotected intermediate was dissolved in 1,4-dioxane (2.0 mL) and treatedwith a 4 M solution of HCl in 1,4-dioxane (2.0 mL, 8.0 mmol). Thereaction was stirred at rt overnight, concentrated in vacuo to afford aresidue which was then precipitated from dithyl ether, filtered andwashed with ether (3×5 mL) to give the title compound as a light yellowsolid (289 mg, yield: 59% as HCl salt). LCMS: RT 0.88 min.; MH+500.3; ¹HNMR (400 MHz, DMSO-d₆) δ: 9.35 (br. s., 2H), 8.74 (s, 1H), 8.51 (t,J=5.65 Hz, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.62-7.80 (m, 2H), 7.30-7.41(m, 1H), 4.26-4.49 (m, 6H), 3.32 (br. s., 2H), 2.36 (s, 3H), 1.97 (br.s., 2H), 1.47 (s, 9H).

Example 226:1-(tert-butyl)-N-(4-(6-((5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

To a solution of1-(tert-butyl)-N-(2-methyl-4-(6-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide(100 mg, 0.20 mmol) and Et₃N (28 uL, 0.20 mmol) in 1,2-dichloroethane (2mL), was added AcOH (11 uL, 0.20 mmol), [1,4]dioxane-2,5-diol (36 mg,0.30 mmol) and then sodium triacetoxyborohydride (84.8 mg, 0.40 mmol).The reaction mixture was stirred at rt for 1 h, diluted with EtOAc, andwashed with saturated aqueous NaHCO₃ and brine. The organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo to afford the crudeproduct which was purified by prep HPLC (CH₃CN/H₂O with 0.05% TFA asmobile phase) to give the title compound as a white powder (48 mg,yield: 37% as TFA salt). LCMS: RT 0.87 min.; MH+544.2; ¹H NMR (400 MHz,DMSO-d₆) δ: 10.38 (br. s., 1H), 10.10 (br. s., 1H), 8.66-8.79 (m, 1H),8.51 (t, J=5.65 Hz, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.72-7.86 (m, 2H),7.58 (br. s., 1H), 7.39 (d, J=8.03 Hz, 1H), 6.77 (br. s., 1H), 4.26-4.83(m, 6H), 3.40-3.86 (m, 4H), 2.98-3.22 (m, 2H), 2.41 (s, 3H), 1.97-2.24(m, 2H), 1.42-1.65 (m, 9H).

Example 227:1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

To a mixture of1-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamidehydrochloride (150 mg, 0.28 mmol) and Et₃N (39 uL, 0.28 mmol) in1,2-dichloroethane (4.0 mL) was added formaldehyde (0.75 mL, 27 mmol)and AcOH (16 uL, 0.28 mmol). The mixture was stirred at rt for 10 min,followed by the addition of sodium triacetoxyborohydride (119 mg, 0.56mmol). The mixture was stirred at rt for 1 h, and concentrated in vacuoto afford the crude material which was purified by prep HPLC (CH₃CN/H₂Owith 0.05% TFA as mobile phase) to give desired product as a lightyellow powder (98 mg, yield: 57% as TFA salt). LCMS: RT 0.80 min.;MH+514.2; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.40 (br. s., 1H), 10.27 (br.s., 1H), 8.73 (s, 1H), 8.51 (t, J=5.65 Hz, 1H), 8.32 (s, 1H), 7.92 (s,1H), 7.72-7.85 (m, 2H), 7.39 (d, J=8.03 Hz, 1H), 6.75 (br. s., 1H),4.29-4.76 (m, 6H), 3.39-3.72 (m, 2H), 2.82 (s, 3H), 2.41 (s, 3H), 2.16(br. s., 1H), 1.99 (br. s., 1H), 1.53 (s, 9H).

Example 228:1-(tert-butyl)-N-(4-(6-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

To a solution of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamidee (85 mg, 0.22 mmol) and6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (62 mg, 0.44 mmol) in2-butanol (5.0 mL) was added a solution of 4 M HCl in 1,4-dioxane (0.10mL, 0.40 mmol) and heated at 50° C. overnight. The reaction was cooledto rt, diluted with EtOAc, and washed with water. The organic layer wasseparated, dried (Na₂SO₄), and concentrated in vacuo to afford a residuewhich was purified by prep HPLC (CH₃CN/H₂O with 0.05% TFA as mobilephase) to give the title compound as light yellow powder (36 mg, yield:28% as TFA salt). RT 1.04 min.; MH+487.2; ¹H NMR (400 MHz, DMSO-d₆) δ:10.59 (br. s., 1H), 8.76 (s, 1H), 8.50 (t, J=5.65 Hz, 1H), 8.32 (d,J=0.75 Hz, 1H), 7.92 (d, J=0.50 Hz, 1H), 7.58-7.81 (m, 3H), 7.40 (d,J=8.03 Hz, 1H), 6.29 (br. s., 1H), 4.68-4.86 (m, 2H), 4.46 (d, J=5.52Hz, 2H), 3.97-4.12 (m, 4H), 2.41 (s, 3H), 1.42-1.62 (m, 9H).

Example 229:3-Ethyl-N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

To a solution of N,N-carbonyldiimidazole (49 mg, 0.30 mmol) in DMF (4.0mL) was added4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (100 mg, 0.30 mmol) and Et₃N (0.13 mL, 0.91 mmol). Themixture was stirred at 35° C. for 2 h, followed by the addition of3-ethylazetidine hydrochloride (55 mg, 0.45 mmol), and then stirred atrt overnight. The mixture was diluted with EtOAc and washed with brine.The organic phase was separated, dried and concentrated in vacuo toafford the crude which was purified by prep HPLC (CH₃CN/H₂O with 0.05%TFA as mobile phase) to give the title compound as a yellow powder (114mg, yield: 76% as TFA salt). LCMS: RT 1.12 min.; MH+406.2; ¹H NMR (400MHz, DMSO-d₆) δ: 9.54 (s, 1H), 8.45 (d, J=5.27 Hz, 1H), 7.93 (d, J=2.01Hz, 3H), 7.56 (br. s., 1H), 7.36 (d, J=8.03 Hz, 1H), 7.27 (d, J=5.27 Hz,1H), 6.75 (br. s., 1H), 4.23 (d, J=4.02 Hz, 2H), 3.91 (t, J=7.91 Hz,2H), 3.83 (s, 3H), 3.45 (dd, J=5.65, 7.91 Hz, 2H), 2.28-2.46 (m, 4H),1.54 (quin, J=7.34 Hz, 2H), 0.83 (t, J=7.28 Hz, 3H).

Example 230:3-(tert-butoxy)-N-(2-methyl-4-(6-((5-methyl-6-oxo-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

1. Synthesis of2-((6-(4-(aminomethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-5-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6(7H)-onehydrochloride

To a solution of tert-butyl4-(6-chloropyrimidin-4-yl)-2-methylbenzylcarbamate (200 mg, 0.60 mmol)and 2-amino-5-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (149 mg,0.9 mmol) in 2-butanol (6.0 mL) was added a solution of 4 M HCl in1,4-dioxane (0.4 mL, 1.5 mmol) and water (1.0 mL). The mixture washeated at 50° C. for 12 h, cooled to rt and concentrated in vacuo toafford a residue which was dissolved in EtOAc and washed with aqueousNaHCO₃ and water. The organic phase was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude material was diluted with diethyl etherand treated with a 4 M solution of HCl in 1,4-dioxane (2.0 mL, 8.0mmol). The reaction was stirred at rt for 4 h to afford a solid whichwas filtered and washed with diethyl ether to give the title compound asa light yellow powder (145 mg, 60% yield: as HCl salt), which was usedin the next step without further purifications. LCMS: RT 0.33 min.;MH+364.1.

2. Synthesis of3-(tert-butoxy)-N-(2-methyl-4-(6-((5-methyl-6-oxo-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)azetidine-1-carboxamide

To a solution of CDI (14 mg, 0.08 mmol) in DMF (2.0 mLl) was added2-[6-(4-aminomethyl-3-methyl-phenyl)-pyrimidin-4-ylamino]-5-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one(30 mg, 0.08 mmoll) and triethylamine (0.03 mL, 0.24 mmol). The mixturewas stirred at 35° C. for 1 h, followed by the addition of3-(tert-butoxy)azetidine hydrochloride (20 mg, 0.12 mmol). The reactionmixture was stirred at rt for 12 h, diluted with MeOH, and filtered. Thefiltrate was concentrated in vacuo to afford the crude produce which waspurified by prep HPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to givethe title compound as an off white powder (12 mg, 25% yield:). LCMS: RT1.00 min.; MH+519.2; ¹H NMR (400 MHz, CD₃OD) δ: 8.84 (s, 1H), 7.60-8.01(m, 3H), 7.51 (d, J=7.78 Hz, 1H), 7.10 (br. s., 1H), 4.52-4.65 (m, 1H),4.40 (s, 4H), 4.10-4.26 (m, 2H), 3.84-3.94 (m, 2H), 3.72-3.83 (m, 2H),3.15 (s, 3H), 2.46 (s, 3H), 1.20 (s, 9H).

Example 231:1-(tert-butyl)-N-(2-chloro-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)-1H-pyrazole-4-carboxamide

A mixture of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (45 mg, 0.27mmol) HATU (113 mg, 0.30 mmol), and DIEA (0.10 mL, 0.54 mmol) in DMF(4.0 mL) was stirred at rt for 5 min, followed by the addition of[6-(4-aminomethyl-3-chloro-phenyl)-pyrimidin-4-yl]-((5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-yl)-amine(100 mg, 0.27 mmol), and the mixture was stirred at rt overnight. Thereaction mixture was then diluted with EtOAc and washed with water. Theorganic phase was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude was purified by silica gel chromatography (EtOAc/heptanegradient) to give the title compound as a white powder (32 mg, yield:22%). LCMS: RT 0.87 min.; MH+520.2; ¹H NMR (400 MHz, DMSO-d₆/CD₃OD) δ:9.97 (s, 1H), 8.56-8.74 (m, 2H), 8.31 (s, 1H), 8.05 (d, J=1.51 Hz, 1H),7.84-7.97 (m, 2H), 7.61 (br. s., 1H), 7.48 (d, J=8.03 Hz, 1H), 6.23 (br.s., 1H), 4.47-4.59 (m, 2H), 3.99 (t, J=5.27 Hz, 2H), 3.65-3.72 (m, 2H),2.82 (t, J=5.52 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 9H).

Example 232:1-(tert-butyl)-N-(4-(64(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

A mixture of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (63 mg, 0.37mmol), HATU (156 mg, 0.41 mmol) and DIEA (0.13 mL, 0.74 mmol) in DMF(6.0 mL) was stirred at rt for 5 min, followed by the addition of[6-(4-aminomethyl-3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-yl)-amine(150 mg, 0.37 mmol). The solution was stirred at rt overnight, dilutedwith EtOAc, washed with water, and the organic phase was separated,dried (Na₂SO₄) and concentrated in vacuo to afford the crude materialwhich was purified by silica gel chromatography(EtOAc/heptane gradient)to give the title compound as a white powder (106 mg, 52% yield:). LCMS:RT 0.96 min.; MH+554.2; ¹H NMR (400 MHz, CD₃OD) δ: 8.61-8.70 (m, 1H),8.36 (s, 1H), 8.29 (s, 1H), 8.18 (d, J=8.28 Hz, 1H), 7.99 (s, 1H),7.58-7.74 (m, 2H), 6.25 (br. s., 1H), 4.80 (s, 2H), 4.12 (t, J=5.65 Hz,2H), 3.68 (s, 2H), 2.98 (t, J=5.65 Hz, 2H), 2.51 (s, 3H), 1.62 (s, 9H).

Example 233:1-(tert-butyl)-N-(4-(6-((5,5-dioxido-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

1. Synthesis of (3-nitropyrazol-5-yl)methanol

To a solution of 3-nitropyrazol-5-carboxylic acid (17 g, 110 mmol) inTHF (200 mL) was slowly added a solution of borane-THF complex (1.0M inTHF, 200 mL) at 0° C. under an atmosphere of nitrogen. The mixture wasthen stirred at rt for 20 hrs, cooled to 0° C., and water (40 mL) and 4NHCl (40 mL) was slowly added and the mixture was stirred at reflux for 1h. The mixture was cooled, was concentrated in vacuo, and extracted withethyl acetate (4×100 mL). The organic phase washed with aqueous NaHCO₃and brine, separated, dried (MgSO₄), filtered, and concentrated in vacuoto afford (3-nitropyrazol-5-yl)methanol (10 g, yield: 64%).

2. Synthesis of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol

A mixture of (3-nitropyrazol-5-yl) MeOH (10 g, 0.07 mol) and cesiumcarbonate (35 g, 0.11 mol) in DMF (100 m)l was heated at 100° C. for 5min and cooled to rt, followed by the addition of dibromoethane (13 g,0.07 mol). The mixture was stirred at rt for 6 h, poured into ice water,to which aqueous citric acid was added to adjust the pH=7. The productwas extracted with EtOAc, washed with water and brine, and the organiclayer was separated, dried (MgSO₄), filtered and concentrated in vacuo.The crude was purified by column chromatography to afford(1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (6 g, yield: 34%).

3. Synthesis of S-(2-(5-(hydroxymethyl)-3-nitro-1H-pyrazol-1-yl)ethyl)ethanethioate

To a solution of (1-bromoethyl-3-nitropyrazol-5-yl) methanol (5.5 g, 22mmol) in DMF (50 ml) was added potassium thioacetate (5.0 g, 44 mmol).The resulting mixture was stirred at 60° C. for 4 hr. The solvent wasreduced to afford a residue which was diluted with DCM and water. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand concentrated in vacuo. The crude was purified by column(DCM/CH₃OH=98/2 as eluent) to affordS-(2-(5-(hydroxymethyl)-3-nitro-1H-pyrazol-1-yl)ethyl) ethanethioate (4g, yield: 74%).

4. Synthesis of S-(2-(5-(hydroxymethyl)-3-nitro-1H-pyrazol-1-yl)ethyl)ethanethioate

A solution of S-(2-(5-(hydroxymethyl)-3-nitro-1H-pyrazol-1-yl)ethyl)ethanethioate (4.0 g, 16.4 mmol) in CH₂Cl₂ (50 mL) was cooled to 0° C.Et₃N (2.5 g, 25 mmol) was added, follow by methanesulfonic chloride (2.2g, 19.2 mmol). The mixture was stirred at 0° C. for 3 hours and washedwith aqueous NaHCO₃. The organic layer was separated, dried over MgSO₄,filtered and concentrated. The crude was purified by column(DCM/CH₃OH=99/1 as eluent) to giveS-(2-(5-(((methylsulfonyl)oxy)methyl)-3-nitro-1H-pyrazol-1-yl)ethyl)ethanethioate (4.2 g, yield: 79%).

5. Synthesis of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine

To a solution ofS-(2-(5-(((methylsulfonyl)oxy)methyl)-3-nitro-1H-pyrazol-1-yl)ethyl)ethanethiolate (4.2 g, 13 mmol) in CH₃OH (60 mL) was added LiOH (0.62 g,26 mmol). The mixture was stirred at rt for 6 hr. The solvent wasreduced and the residue was diluted with CH₂Cl₂ and water. The organiclayer was separated, washed with brine, then dried (MgSO₄), filtered andconcentrated in vacuo to afford the crude which was purified by column(CH₂Cl₂ as eluent) to give2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine (2.0 g, yield: 83%).

6. Synthesis of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine5,5-dioxide

To a solution of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine(1.3 g, 7 mmol) in CH₃OH (150 mL) was added a solution of oxone (12 g)in water (150 mL). The reaction was stirred at rt for 8 hr. The solventwas reduced and the resulting aqueous mixture was extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered andconcentrated in vacuo to afford the crude2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine 5,5-dioxide (1.5 g)which was used in the next step without further purifications.

7. Synthesis of 2-amino-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine

A 500 ml hydrogenation flask was charged with2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine 5,5-dioxide (1.2 g,5.5 mmol), CH₃OH (200 ml) and 10% palladium on carbon (50% wet, 400 mg).The flask was placed under an atmosphere of hydrogen to pressure 35 psiand stirred at rt for 1 h. The mixture was filtrated through a pad ofcelite and washed with MeOH. The filtrate was concentrated in vacuo toafford 2-amino-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine 5,5-dioxide(700 mg, yield: 68%). MH+188.0; ¹H NMR (400 MHz, DMSO-d₆) δ: 5.44 (s,1H), 4.53 (s, 2H), 4.24 (t, J=6.02 Hz, 2H), 3.70 (t, J=5.90 Hz, 2H).

8. Synthesis of1-(tert-butyl)-N-(4-(6-((5,5-dioxido-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

A mixture of1-(tert-butyl)-N-(4-(6-chloropyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide(100 mg, 0.26 mmol), 2-amino-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine5,5-dioxide (98 mg, 0.52 mmol) and 4 M solution of HCl in 1,4-dioxane(0.07 mL, 0.26 mmol) in 2-butanol (2.0 mL) and water (2.0 mL) was heatedat 50° C. for 12 h. The reaction was then cooled to rt, diluted withEtOAc and washed with water. The organic layer was separated, dried(Na₂SO₄), and concentrated in vacuo to afford the crude which waspurified by silica gel chromatography (DCM+1% to 10% 2M NH₃/MeOH) togive the title compound as yellow powder (88 mg, yield: 62%). LCMS: RT0.99 min.; MH+535.2; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.11 (s, 1H), 8.67(d, J=0.50 Hz, 1H), 8.46 (t, J=5.65 Hz, 1H), 8.32 (s, 1H), 7.92 (s, 1H),7.73-7.88 (m, 2H), 7.62 (br. s., 1H), 7.37 (d, J=8.03 Hz, 1H), 6.45 (br.s., 1H), 4.72 (s, 2H), 4.37-4.58 (m, 4H), 3.82 (t, J=5.65 Hz, 2H), 2.40(s, 3H), 1.53 (s, 9H).

Example 234:(S)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamideand(R)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide

3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrazin-2-yl)amino)-pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide)(6.7 g, 9.2 mmol) was separated by chiral column. The following SFCmethod was used: AS-H (2×25 cm) 30% ACN:ethanol/CO₂, 100 bar; 60 mL/min,220 nm.; inj vol.: 2 mL, 20 mg/mL DCM:CH₃OH (1% DEA). Two isomers wereobtained: 2.7 g of(S)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.04 min.; MH+503.2; ¹H NMR (400MHz, CD₃OD) δ: 8.85 (br. s., 1H), 8.36 (s, 1H), 7.63-7.75 (m, 2H), 7.54(d, J=8.03 Hz, 1H), 7.24 (s, 1H), 6.96 (s, 1H), 6.15-6.37 (m, 1H),4.36-4.77 (m, 6H), 3.95 (br. s., 2H), 3.53-3.63 (m, 1H), 3.43-3.52 (m,1H), 3.06-3.19 (m, 4H), 2.41-2.53 (m, 3H), 2.06-2.20 (m, 1H), 1.88-2.00(m, 1H), 1.63-1.80 (m, 2H), 0.77-1.08 (m, 9H); and 2.3 g of(R)-3-(tert-butyl)-N-(2-methyl-4-(6-((5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-yl)amino)pyrimidin-4-yl)benzyl)pyrrolidine-1-carboxamide(chemical purity>99%, ee>99%). LCMS: RT 1.03 min.; MH+503.2; ¹H NMR (400MHz, METHANOL-d₄) δ: 8.85 (br. s., 1H), 8.36 (s, 1H), 7.62-7.77 (m, 2H),7.54 (d, J=7.78 Hz, 1H), 7.25 (br. s., 1H), 6.98 (br. s., 1H), 6.26 (s,1H), 4.44 (d, J=5.77 Hz, 5H), 3.83-4.05 (m, 2H), 3.53-3.64 (m, 1H),3.43-3.53 (m, 1H), 3.16 (s, 4H), 2.48 (s, 3H), 2.23-2.40 (m, 1H),2.06-2.19 (m, 1H), 1.88-2.01 (m, 1H), 1.63-1.80 (m, 2H), 0.76-1.09 (m,9H). The chiral center was confirmed by VCD study.

Example 235:1-(tert-butyl)-N-(4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide

A mixture of 1-tert-Butyl-1H-pyrazole-4-carboxylic acid4-(6-chloro-pyrimidin-4-yl)-2-methyl-benzylamide (215 mg, 0.560 mmol)and 1-Ethyl-1H-pyrazol-4-ylamine (80.9 mg, 0.73 mmol) in PhCH₃ (6.7 mL,63 mmol) was degassed for 5 min,2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (45.98 mg, 0.112 mmol)and tris(dibenzylideneacetone)dipalladium(0) (51.3 mg, 0.056 mmol) andsodium tert-butoxide (161.5 mg, 1.68 mmol) were then added, degassed foranother 5 min, and the reaction was heated in a microwave at 100° C.overnight. The reaction was then cooled to rt, diluted with EtOAc, andwashed with water. The organic layer was separated, dried (Na₂SO₄), andconcentrated in vacuo to afford the crude which was purified by prepHPLC (CH₃CN/H₂O with 0.05% TFA as mobile phase) to give the desiredproduct as yellow powder. ¹H NMR (400 MHz, CD₃OD) δ: ppm 8.21-8.34 (m,2H) 7.97 (m, J=6.80 Hz, 4H) 7.69 (s, 1H) 7.42 (t, J=7.80 Hz, 2H) 4.58(s, 2H) 4.19 (dd, J=8.03, 7.28 Hz, 2H) 3.35 (s, 2H) 2.43 (s, 3H) 1.60(s, 9H) 1.48 (t, J=7.28 Hz, 3H).

Example 236:3-(tert-butoxy)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)azetidine-1-carboxamide

1. Synthesis of N-(3-bromophenethyl)-4-methylbenzenesulfonamide

To a mixture of 2-(3-bromophenyl)ethanamine (2 g, 10 mmol) in CH₂Cl₂ (10mL), TEA (2.02 g, 20 mmol) and TsCl (2.18 g, 11.5 mmol) were added at 0°C. The mixture was stirred at rt for 2 h, diluted with NaOH (1N, 100 mL)and extracted with CH₂Cl₂ (100 mL). The organic layer was washed withwater (100 mL), brine (100 mL), dried (Na₂SO₄) and concentrated in vacuoto give N-(3-bromophenethyl)-4-methylbenzenesulfonamide (3.5 g, yield:100%) as a yellow oil. ESI-MS (M+H)⁺: 354.0. ¹H NMR (400 MHz, CDCl₃) δ:7.69 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H),7.17 (t, J=1.6 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.03-7.02 (m, 1H), 4.52(t, J=6.0 Hz, 1H), 3.22-3.17 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.45 (s,3H).

2. Synthesis of ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate

To a mixture of N-(3-bromophenethyl)-4-methylbenzenesulfonamide (7.2 g,20 mmol) in (CH₃)₂C₀ (80 mL), K₂CO₃ (19.3 g, 140 mmol) and ethyl2-bromoacetate (3.67 g, 22 mmol) were added. The mixture was stirred at60° C. for 12 h, cooled to rt and the salt was filtered out. Theresulting filtrate was concentrated in vacuo to give ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 g,yield: 100%) as a yellow oil. ESI-MS (M+H)⁺: 440.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.70 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.0Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.10-7.08 (m, 2H), 4.08 (q, J=7.6 Hz,2H), 3.98 (s, 2H), 3.44 (t, J=7.6 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.42(s, 3H), 1.19 (t, J=7.2 Hz, 3H).

3. Synthesis of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)aceticAcid

To a solution of ethyl2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 mg, 20mmol) in EtOH (40 mL) and H₂O (40 mL) was added NaOH (1.6 g, 40 mmol).The reaction mixture was stirred at rt for 12 h. Then the solvent wasreduced and the residue was adjusted to pH=3 with HCl (1 N). The mixturewas extracted with EtOAc (100 mL×3). The organic layers were dried over(Na₂SO₄) and concentrated in vacuo to give2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid as ayellow solid (8.2 g, yield: 100%). ESI-MS (M+H)⁺: 412.0. ¹H NMR (400MHz, CDCl₃) δ: 7.69 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.29 (d,J=8.4 Hz, 2H), 7.22 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.08-7.06 (m, 1H),4.00 (s, 2H), 3.45 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.42 (s,3H).

4. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one

To a solution of2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid (8.2 g, 20mmol) in CH₂Cl₂ (100 mL) was added SOCl₂ (11.9 g, 100 mmol) and DMF(cat.). The reaction mixture was stirred at 40° C. for 1 h. Then thesolvent was removed under reduced pressure and dried in vacuo for 2 h.The residue was dissolved in CH₂Cl₂ (100 mL) and cooled in an ice bath.AlCl₃ (10.56 g, 80 mmol) was added and the mixture was stirred at 0°C.-rt for 12 h. The mixture was poured into conc. HCl (20 mL) andextracted with EtOAc (100 mL×2). The organic layers were washed withwater (100 mL), brine (100 mL), dried (Na₂SO₄), and concentrated invacuo to afford a residue which was purified by silica gel column(petroleum ether:EtOAc=4:1) to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one as a yellowsolid (1.88 g, yield: 24%). ESI-MS (M+H)⁺: 394.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.42 (d, J=8.4 Hz, 2H), 7.38 (dd, J=8.4, 1.6 Hz, 1H),7.31-7.29 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 3.68 (t, J=6.8Hz, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.39 (s, 3H).

5. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine was similarto that of Example 180. The residue was purified by silica gel column(CH₂Cl₂:MeOH=20:1) to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine as a yellowsolid (154 mg, yield: 64%). ESI-MS (M+H)⁺: 395.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.66 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (dd,J=8.4, 1.6 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),4.12-4.40 (m, 1H), 3.42-3.36 (m, 2H), 3.19-3.12 (m, 2H), 2.96-2.89 (m,2H), 2.41 (s, 3H).

6. Synthesis of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

A mixture of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (1.2 g,3.04 mmol) in HBr/HOAc (33%, 20 mL) was stirred at 70° C. for 12 h.After cooling down, the mixture was diluted with EtOAc (60 mL) and theresulting precipitate was filtered and dried under vacuum to give7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (870 mg,yield: 71%) as a white solid. ESI-MS (M+H)⁺: 241.1. ¹H NMR (400 MHz,CDCl₃) δ: 7.65-7.63 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 5.17-5.14 (m, 1H),3.84-3.80 (m, 1H), 3.69-3.65 (m, 1H), 3.44-3.40 (m, 2H), 3.27-3.14 (m,2H).

7. Synthesis of tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To a mixture of7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (680 mg,1.7 mmol) and TEA (515 mg, 5.1 mmol) in CH₂Cl₂ (10 mL), Boc₂O (333 mg,1.0 mmol) was added. The mixture was stirred at rt for 2 h. Afterdiluting with CH₂Cl₂ (100 mL), the organic layer was washed with water(30 mL) and brine (30 mL), dried (Na₂SO₄), filtered and concentrated invacuo to give tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (450mg, yield: 77%) as a yellow oil. ESI-MS (M+H)⁺: 341.0. ¹H NMR (400 MHz,CDCl₃) δ: 7.31 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.19-7.11 (m, 1H),4.17-4.10 (m, 1H), 3.83-3.66 (m, 2H), 3.48-3.45 (m, 1H), 3.37-3.14 (m,2H), 2.78-2.73 (m, 1H), 1.47 (s, 9H).

8. Synthesis of tert-butyl7-bromo-1-(3-(tert-butoxy)azetidine-1-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To a mixture of tert-butyl1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (300mg, 0.88 mmol) in DMF (4 mL), CDI (142 mg, 0.88 mmol) and DIPEA (227 mg,1.76 mmol) was added. The mixture was stirred at rt for 1 h before3-(tert-butoxy)azetidine HCl (145 mg, 0.88 mmol) was added and thesolution was stirred at rt for another 4 h. The mixture was purified byprep-HPLC (MeCN/water with 0.05% NH₄HCO₃ mobile phase) to givetert-butyl7-bromo-1-(3-(tert-butoxy)azetidine-1-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(300 mg, yield: 69%) as a white solid. ESI-MS (M+H)⁺: 496.2. ¹H NMR (400MHz, CD₃OD) δ: 7.37-7.34 (m, 2H), 7.19 (d, J=8.0 Hz, 1H), 5.04 (t, J=6.4Hz, 1H), 4.60-4.51 (m, 1H), 4.18-4.12 (m, 2H), 3.78-3.75 (m, 2H),3.67-3.55 (m, 4H), 3.17-2.91 (m, 2H), 1.42-1.36 (m, 9H), 1.19 (s, 9H).

9. Synthesis of Cert-butyl1-(3-(tert-butoxy)azetidine-1-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

Synthesis of tert-butyl1-(3-(tert-butoxy)azetidine-1-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylatewas similar to that of Example 157. The mixture was concentrated andpurified by silica gel column (CH₂Cl₂: MeOH=40:1) to give tert-butyl1-(3-(tert-butoxy)azetidine-1-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(200 mg, yield: 56%) as a yellow solid. ESI-MS (M+H)⁺: 591.3. ¹H NMR(400 MHz, CD₃OD) δ: 8.40 (d, J=5.2 Hz, 1H), 7.99-7.97 (m, 2H), 7.94 (s,1H), 7.64 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 5.16(t, J=5.6 Hz, 1H), 4.61-4.54 (m, 1H), 4.21-4.15 (m, 2H), 3.89 (s, 3H),3.81-3.62 (m, 6H), 3.28-3.03 (m, 2H), 1.43-1.34 (m, 9H), 1.20 (s, 9H).

10. Synthesis of3-(tert-butoxy)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)azetidine-1-carboxamide

Synthesis of3-(tert-butoxy)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)azetidine-1-carboxamidewas similar to that of Example 180. The residue was purified by silicagel chromatography (CH₂Cl₂: MeOH=10:1) to give3-(tert-butoxy)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)azetidine-1-carboxamide(53 mg, yield: 49%). ESI-MS (M+H)⁺: 491.2. ¹H NMR (400 MHz, CD₃OD) δ:8.40 (d, J=5.2 Hz, 1H), 7.96-7.94 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H),7.40 (d, J=8.0 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 5.06 (d, J=7.2 Hz, 1H),4.62-4.56 (m, 1H), 4.21-4.19 (m, 2H), 3.89 (s, 3H), 3.84-3.79 (m, 2H),3.13-2.84 (m, 6H), 1.12 (s, 9H).

Example 237:4-isobutyl-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-2-one

1. The preparation of tert-butyl4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate

To a solution of (4-bromo-2-methylphenyl)methanol (1.3 g, 6.7 mmol) inCH₂Cl₂ (50 mL) was added PBr₃ (0.95 mL, 10 mmol) at 0° C. The mixturewas stirred at rt for 1 h, quenched with ice-water (50 mL) and the pHvalue was adjusted to 7.0 with 50% aqueous NaOH solution. The mixturewas extracted with EtOAc (100 mL×2) and the combined organic layers werewashed with water (50 mL), dried (Na₂SO₄) and concentrated in vacuo togive 4-bromo-1-(bromomethyl)-2-methylbenzene (1.56 g, yield: 89%) as awhite solid which was used in next step without further purification.

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1.2 g, 6.0mmol) in THF (200 mL) was added NaH (320 mg, 8.1 mmol) with ice-bathcooling. After stirring at 0° C. for 1 h, a solution of4-bromo-1-(bromomethyl)-2-methylbenzene (1.42 g, 5.4 mmol) in THF (5 mL)was added dropwise over a period of 10 min, the ice-bath was removed andthe mixture was stirred at rt for 2 h. The mixture was diluted withice-water (50 mL) and extracted with EtOAc (100 mL×2) and the combinedorganic phases were washed with brine (50 mL), dried (Na₂SO₄) andconcentrated in vacuo to afford a residue which was purified by silicagel column (petroleum ether/EtOAc=5:1) to give tert-butyl4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate (1.6 g, yield:77%) as white solid. ESI-MS (M+H-56)⁺: 327.0. ¹H NMR (400 MHz, CDCl₃) δ:7.34 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.61 (s,2H), 4.16 (s, 2H), 3.60 (t, J=5.2 Hz, 2H), 3.24 (t, J=5.2 Hz, 2H), 2.27(s, 3H), 1.47 (s, 9H).

2. The preparation of1-(4-bromo-2-methylbenzyl)-4-isobutylpiperazin-2-one

Synthesis of 1-(4-bromo-2-methylbenzyl)-4-isobutylpiperazin-2-one wassimilar to that of Example 199. The organic phase was concentrated andthe crude was purified by prep-HPLC (CH₃CN/H₂O with 0.05% NH₄OH asmobile phase) to give1-(4-bromo-2-methylbenzyl)-4-isobutylpiperazin-2-one as a yellow oil(120 mg, yield: 79%). ESI-MS (M+H)⁺: 339.1. ¹H NMR (400 MHz, CDCl₃) δ:7.31 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.0, 2.0 Hz, 1H), 6.99 (d, J=8.0 Hz,1H), 4.57 (s, 2H), 3.18 (s, 2H), 3.14 (t, J=5.2 Hz, 2H), 2.60 (t, J=5.6Hz, 2H), 2.27 (s, 3H), 2.14 (d, J=7.2 Hz, 2H), 1.80-1.73 (m, 1H), 0.90(d, J=6.8 Hz, 6H).

3. The preparation of4-isobutyl-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-2-one

Synthesis of4-isobutyl-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-2-onewas similar to that of Example 157. The crude was purified by silica gelcolumn (petroleum ether/EtOAc=1:1=1:4) to give4-isobutyl-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-2-oneas a yellow solid (180 mg, yield: 69%). ESI-MS (M+H)⁺: 434.2. ¹H NMR(400 MHz, CDCl₃) δ: 8.43 (d, J=4.8 Hz, 1H), 7.88 (s, 1H), 7.85-7.83 (m,2H), 7.55 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.09 (br, 1H), 7.07 (d, J=5.6Hz, 1H), 4.69 (s, 2H), 3.92 (s, 3H), 3.22 (s, 2H), 3.20 (t, J=5.6 Hz,2H), 2.62 (t, J=5.6 Hz, 2H), 2.39 (s, 3H), 2.16 (d, J=7.6 Hz, 2H),1.81-1.74 (m, 1H), 0.91 (d, J=6.8 Hz, 6H).

Example 238

The following compounds I-250 through I-360 can be synthesized accordingto the procedures described in Examples 1-237.

Chemical name Compound# H-NMR MH+ 1-tert-butyl-N-[[4-[2-[[1-(2- I-250 ¹HNMR (400 MHz, METHANOL-d₄) 475.1 hydroxyethyl)pyrazol-4- δ ppm 8.68 (s,1 H) 8.19 (s, 1 H) 7.97 yl]amino]pyrimidin-4-yl]-2- (s, 1 H) 7.71 (s, 1H) 7.63 (br. s., 1 H) methyl- 7.48 (s, 1 H) 7.03 (s, 1 H) 4.59 (s, 2 H)phenyl]methyl]pyrazole-4- 4.26 (s, 1 H) 3.91-3.98 (m, 1 H) 2.48carboxamide (s, 1 H) 1.62 (s, 4H). 3-tert-butoxy-N-[[2-methyl-4- I-251¹H NMR (400 MHz, METHANOL-d₄) [6-[[5-(4-methylpiperazin-1- δ ppm 8.85(br. s., 1 H) 8.72 (br. s., 1 yl)-2- H) 7.98 (br. s., 2 H) 7.91 (br. s.,1 H) pyridyl]amino]pyrimidin-4- 7.76-7.88 (m, 3 H) 7.81 (br. s., 1 H)yl]phenyl]methyl]azetidine-1- 7.42 (br. s., 1 H) 4.51 (br. s., 1 H) 4.41carboxamide (br. s., 2 H) 4.16 (d, J = 7.03 Hz, 2 H) 3.87 (br. s., 2 H)2.99 (d, J = 2.01 Hz, 3 H) 2.91 (dd, J = 15.44, 1.88 Hz, 4H) 2.42 (br.s., 3 H) 1.20 (d, J = 2.26 Hz, 9 H). 1-tert-butyl-N-[[2-methyl-4- I-2521H NMR (400 MHz, METHANOL-d4) 445.2 [2-[(1-methylpyrazol-4- δ ppm 8.34(d, J = 6.02 Hz, 1H), 8.00- yl)amino]pyrimidin-4- 8.12 (m, 2H), 7.98 (s,1H), 7.83 (s, 1H), yl]phenyl]methyl]pyrazole-3- 7.68 (s, 1H), 7.48 (d, J= 8.03 Hz, 1H), carboxamide 7.41 (br. s., 1H), 6.76 (d, J = 2.51 Hz,1H), 4.67 (s, 2H), 3.94 (s, 3H), 2.51 (s, 3H), 1.65 (s, 9H).(3R)-3-tert-butyl-N-[[2- I-253 1H NMR (400 MHz, METHANOL-d4) 448.2methyl-4-[2-[(1- δ ppm 8.40 (d, J = 5.27 Hz, 1H), 7.98 methylpyrazol-4-(s, 1H), 7.94 (br. s., 2H), 7.66 (s, 1H), yl)amino]pyrimidin-4- 7.42 (d,J = 8.53 Hz, 1H), 7.21 (d, J = yl]phenyl]methyl]pyrrolidine- 5.27 Hz,1H), 4.59 (br. s., 1H), 4.32- 1-carboxamide 4.52 (m, 2H), 3.91 (s, 3H),3.59 (t, J = 8.91 Hz, 1H), 3.44-3.53 (m, 1H), 3.04- 3.19 (m, 1H), 2.45(s, 3H), 1.59-2.26 (m, 2H), 0.98 (s, 9H). (3S)-3-tert-butyl-N-[[2- I-2541H NMR (400 MHz, METHANOL-d4) 448.2 methyl-4-[2-[(1- δ ppm 8.40 (d, J =5.27 Hz, 1H), 7.98 methylpyrazol-4- (s, 1H), 7.94 (br. s., 2H), 7.66 (s,1H), yl)amino]pyrimidin-4- 7.42 (d, J = 8.53 Hz, 1H), 7.21 (d, J =yl]phenyl]methyl]pyrrolidine- 5.27 Hz, 1H), 4.59 (br. s., 1H), 4.33-1-carboxamide 4.52 (m, 2H), 3.91 (s, 3H), 3.59 (t, J = 8.91 Hz, 1H),3.43-3.53 (m, 1H), 3.03- 3.19 (m, 1H), 2.45 (s, 3H), 1.63-2.25 (m, 2H),0.98 (s, 9H). (3S)-3-isopropyl-N-[[2- I-255 1H NMR (400 MHz,METHANOL-d4) 434.2 methyl-4-[2-[(1- δ ppm 8.40 (d, J = 5.27 Hz, 1H),7.99 methylpyrazol-4- (s, 1H), 7.94 (br. s., 2H), 7.66 (s, 1H),yl)amino]pyrimidin-4- 7.42 (d, J = 8.53 Hz, 1H), 7.21 (d, J =yl]phenyl]methyl]pyrrolidine- 5.27 Hz, 1H), 6.52-6.72 (m, 1H), 4.31-1-carboxamide 4.52 (m, 2H), 3.91 (s, 3H), 3.45-3.73 (m, 2H), 3.38 (br.s., 1H), 2.99 (t, J = 9.79 Hz, 1H), 2.45 (s, 3H), 1.38-2.23 (m, 4H),1.01 (d, J = 8.03 Hz, 6H). 3-tert-butoxy-N-[[2-methyl-4- I-256 1H NMR(300 MHz, METHANOL-d4) 506.3 [6-[(5-methyl-6,7-dihydro- δ ppm 8.81 (s,1H), 7.63-7.88 (m, 3H), 4H-pyrazolo[1,5-a]pyrazin-2- 7.51 (d, J = 7.93Hz, 1H), 6.61 (br. s., yl)amino]pyrimidin-4- 1H), 4.60 (s, 3H), 4.47 (t,J = 5.85 Hz, yl]phenyl]methyl]azetidine-1- 2H), 4.40 (s, 2H), 4.11-4.24(m, 2H), carboxamide 3.88 (br. s., 2H), 3.79 (dd, J = 4.91, 9.06 Hz,2H), 3.12 (s, 3H), 2.46 (s, 3H), 1.21 (s, 9H). 1-tert-butyl-N-[2-[2-[(1-I-257 1H NMR (400 MHz, METHANOL-d4) 485.1 methylpyrazol-4- δ ppm 8.66(d, J = 7.78 Hz, 1H), 8.27- yl)amino]pyrimidin-4-yl]- 8.47 (m, 2H), 8.08(s, 1H), 7.98 (d, J = 6,7,8,9-tetrahydro-5H- 12.55 Hz, 3H), 7.68 (s,1H), 7.31-7.46 benzo[7]annulen-5- (m, 2H), 5.38 (d, J = 10.54 Hz, 1H),yl]pyrazole-4-carboxamide 3.93 (s, 3H), 2.91-3.23 (m, 2H), 1.76- 2.21(m, 5H), 1.65 (s, 9H), 1.26-1.55 (m, 1H) 1-tert-butyl-N-[[4-[2-[(1-I-258 1H NMR (400 MHz, DMSO-d6) δ ppm 473.2 isopropylpyrazol-4- 9.49 (s,1H), 8.41-8.54 (m, 2H), 8.32 yl)amino]pyrimidin-4-yl]-2- (s, 1H),7.86-8.09 (m, 4H), 7.56 (s, methyl- 1H), 7.39 (d, J = 8.03 Hz, 1H), 7.25(d, phenyl]methyl]pyrazole-4- J = 5.27 Hz, 1H), 4.39-4.54 (m, 3H),carboxamide 2.41 (s, 3H), 1.53 (s, 9H), 1.42 (d, J = 6.53 Hz, 6H).3-isopropoxy-N-[[4-[2-[(1- I-259 1H NMR (400 MHz, DMSO-d6) δ ppm 464.2isopropylpyrazol-4- 9.48 (s, 1H), 8.45 (d, J = 5.27 Hz, 1H),yl)amino]pyrimidin-4-yl]-2- 7.83-8.06 (m, 3H), 7.56 (s, 1H), 7.35methyl- (d, J = 8.03 Hz, 1H), 7.25 (d, J = 5.27phenyl]methyl]azetidine-1- Hz, 1H), 6.85 (t, J = 5.52 Hz, 1H), 4.47carboxamide (quin, J = 6.65 Hz, 1H), 4.28-4.37 (m, 1H), 4.23 (d, J =5.52 Hz, 2H), 3.96- 4.12 (m, 2H), 3.50-3.68 (m, 3H), 2.37 (s, 3H), 1.43(d, J = 6.78 Hz, 6H), 1.08 (d, J = 6.02 Hz, 6H).1-tert-butyl-N-[[4-[2-[(1- I-260 1H NMR (400 MHz, DMSO-d6) δ ppm 471cyclopropylpyrazol-4- 9.50 (s, 1H), 8.41-8.52 (m, 2H), 8.33yl)amino]pyrimidin-4-yl]-2- (s, 1H), 7.86-8.06 (m, 4H), 7.53 (br. s.,methyl- 1H), 7.39 (d, J = 8.03 Hz, 1H), 7.26 (d,phenyl]methyl]pyrazole-4- J = 5.02 Hz, 1H), 4.47 (d, J = 5.52 Hz,carboxamide 2H), 3.65-3.76 (m, 1H), 2.42 (s, 3H), 1.53 (s, 9H),0.88-1.08 (m, 4H). N-[[4-[2-[(1-ethylpyrazol-4- I-262 1H NMR (400 MHz,DMSO-d6) δ ppm 456.2 yl)amino]pyrimidin-4-yl]-2- 9.48 (s, 1H), 8.45 (d,J = 5.02 Hz, 1H), methyl-phenyl]methyl]-3- 7.85-8.02 (m, 3H), 7.56 (br.s., 1H), (1,1,1,3,3,3-d6)isopropoxy- 7.35 (d, J = 8.28 Hz, 1H), 7.25 (d,J = azetidine-1-carboxamide 5.27 Hz, 1H), 6.84 (t, J = 5.65 Hz, 1H),4.27-4.37 (m, 1H), 4.23 (d, J = 5.52 Hz, 2H), 4.00-4.17 (m, 4H), 3.62(dd, J = 4.64, 8.91 Hz, 2H), 3.55 (s, 1H), 2.36 (s, 3H), 1.38 (t, J =7.15 Hz, 3H). N-[[2-methyl-4-[2-[(1- I-263 1H NMR (400 MHz, DMSO-d6) δppm 420.1 methylpyrazol-4- 9.50 (s, 1H), 8.45 (d, J = 5.27 Hz, 1H),yl)amino]pyrimidin-4- 7.92 (d, J = 2.26 Hz, 3H), 7.55 (br. s.,yl]phenyl]methyl]-3-propyl- 1H), 7.35 (d, J = 8.28 Hz, 1H), 7.25 (d,azetidine-1-carboxamide J = 5.02 Hz, 1H), 6.74 (t, J = 5.52 Hz, 1H),4.22 (d, J = 5.27 Hz, 2H), 3.91 (t, J = 7.91 Hz, 2H), 3.83 (s, 3H), 3.45(dd, J = 5.77, 7.78 Hz, 2H), 2.36 (s, 3H), 1.52 (q, J = 7.53 Hz, 2H),1.24 (sxt, J = 7.43 Hz, 2H), 0.88 (t, J = 7.28 Hz, 3H).5-tert-butyl-N-[[2-methyl-4- I-264 1H NMR (400 MHz, METHANOL-d4) 447.2[2-[(1-methylpyrazol-4- δ ppm 9.37 (br. s., 1H), 8.33 (d, J = 5.77yl)amino]pyrimidin-4- Hz, 1H), 7.91-8.10 (m, 3H), 7.67 (s,yl]phenyl]methyl]-1,2,4- 1H), 7.48 (d, J = 8.03 Hz, 1H), 7.40 (d,oxadiazole-3-carboxamide J = 6.02 Hz, 1H), 4.63-4.71 (m, 2H), 3.92 (s,3H), 2.50 (s, 3H), 1.49 (s, 9H). 5-tert-butyl-N-[[2-methyl-4- I-265 1HNMR (400 MHz, METHANOL-d4) 501.3 [6-[(5-methyl-6,7-dihydro- δ ppm 9.16(t, J = 5.65 Hz, 1H), 8.78 (s, 4H-pyrazolo[1,5-a]pyrazin-2- 1H),7.62-7.83 (m, 2H), 7.52 (d, J = yl)amino]pyrimidin-4- 8.03 Hz, 1H),6.43-6.67 (m, 2H), 4.52- yl]phenyl]methyl]isoxazole- 4.74 (m, 4H), 4.44(t, J = 5.77 Hz, 3-carboxamide 2H), 3.76-3.92 (m, 2H), 3.09 (s, 3H),2.51 (s, 3H), 1.39 (s, 9H). 2-tert-butyl-N-[[2-methyl-4- I-266 1H NMR(400 MHz, METHANOL-d4) 514.2 [6-(5,6,7,8-tetrahydro-1,6- δ ppm 9.11 (t,J = 5.65 Hz, 1H), 8.88 (s, naphthyridin-2- 1H), 8.42 (br. s., 1H), 8.24(s, 1H), 7.76- ylamino)pyrimidin-4- 7.86 (m, 2H), 7.73 (d, J = 8.53 Hz,yl]phenyl]methyl]thiazole-5- 1H), 7.47-7.63 (m, 2H), 4.64 (s, 2H),carboxamide 4.41 (s, 2H), 3.65 (t, J = 6.40 Hz, 2H), 3.23-3.28 (m, 2H),2.52 (s, 3H), 1.47 (s, 9H). 2-tert-butyl-N-[[2-methyl-4- I-267 1H NMR(400 MHz, METHANOL-d4) 514.3 [6-(5,6,7,8-tetrahydro-2,7- δ ppm 9.09 (s,1H), 8.89 (s, 1H), 8.35 naphthyridin-3- (s, 1H), 8.24 (s, 1H), 8.13 (br.s., 1H), ylamino)pyrimidin-4- 7.75-7.85 (m, 2H), 7.61 (s, 1H), 7.53yl]phenyl]methyl]thiazole-5- (d, J = 8.03 Hz, 1H), 4.64 (s, 2H), 4.44carboxamide (s, 2H), 3.57 (t, J = 6.40 Hz, 2H), 3.22 (t, J = 6.40 Hz,2H), 2.51 (s, 3H), 1.46 (s, 9H). 2-tert-butyl-N-[[4-[6-[[7-(2- I-268 1HNMR (400 MHz, METHANOL-d4) 558.3 hydroxyethyl)-6,8-dihydro- δ ppm 9.08(s, 1H), 8.87 (s, 1H), 8.33 5H-2,7-naphthyridin-3- (s, 1H), 8.24 (s,1H), 8.12 (s, 1H), 7.76- yl]amino]pyrimidin-4-yl]-2- 7.87 (m, 2H), 7.68(s, 1H), 7.52 (d, J = methyl- 8.03 Hz, 1H), 4.50-4.70 (m, 3H), 3.94-phenyl]methyl]thiazole-5- 4.04 (m, 2H), 3.42-3.51 (m, 2H), carboxamide2.66 (s, 6H), 2.51 (s, 3H), 1.46 (s, 9H). 2-tert-butyl-N-[[2-methyl-4-I-269 1H NMR (400 MHz, METHANOL-d4) 528.3 [6-[(7-methyl-6,8-dihydro- δppm 9.08 (br. s., 1H), 8.86 (d, J = 1.00 5H-2,7-naphthyridin-3- Hz, 1H),8.31 (s, 1H), 8.24 (s, 1H), 8.10 yl)amino]pyrimidin-4- (s, 1H),7.77-7.86 (m, 2H), 7.70 (s, yl]phenyl]methyl]thiazole-5- 1H), 7.51 (d, J= 8.03 Hz, 1H), 4.63 (s, carboxamide 2H), 4.51 (br. s., 2H), 3.52-3.78(m, 4H), 3.10 (s, 3H), 2.50 (s, 3H), 1.46 (s, 9H).2-tert-butyl-N-[[2-methyl-4- I-270 1H NMR (400 MHz, METHANOL-d4) 503.4[6-(4,5,6,7- δ ppm 9.11 (t, J = 5.77 Hz, 1H), 8.80 (d,tetrahydropyrazolo[1,5- J = 1.00 Hz, 1H), 8.23 (s, 1H), 7.63-a]pyrazin-2- 7.79 (m, 3H), 7.54 (d, J = 8.03 Hz, 1H),ylamino)pyrimidin-4- 6.61 (br. s., 1H), 4.61-4.67 (m, 2H),yl]phenyl]methyl]thiazole-5- 4.56 (s, 2H), 4.42 (t, J = 5.90 Hz, 2H),carboxamide 3.78-3.88 (m, 2H), 2.51 (s, 3H), 1.46 (s, 9H).2-tert-butyl-N-[[4-[6-[[5-(2- I-271 1H NMR (400 MHz, METHANOL-d4) 547.4hydroxyethyl)-6,7-dihydro- δ ppm 8.82 (s, 1H), 8.24 (s, 1H), 7.67-4H-pyrazolo[1,5-a]pyrazin-2- 7.83 (m, 3H), 7.52-7.57 (m, 1H), 6.56-yl]amino]pyrimidin-4-yl]-2- 6.68 (m, 1H), 4.64 (s, 4H), 4.42-4.55methyl- (m, 2H), 3.89-4.06 (m, 4H), 3.44- phenyl]methyl]thiazole-5- 3.56(m, 2H), 2.51 (s, 3H), 1.46 (s, 9H). carboxamide3-isopropoxy-N-[[2-methyl-4- I-272 1H NMR (400 MHz, DMSO-d6) δ ppm 477.2[6-(4,5,6,7- 9.55 (br. s., 2H), 8.73 (s, 1H), 7.70-tetrahydropyrazolo[1,5- 7.83 (m, 2H), 7.36 (d, J = 8.28 Hz, 1H),a]pyrazin-2- 6.87 (t, J = 5.65 Hz, 1H), 4.43 (br. s.,ylamino)pyrimidin-4- 2H), 4.18-4.36 (m, 5H), 3.98-4.10yl]phenyl]methyl]azetidine-1- (m, 2H), 3.49-3.75 (m, 5H), 2.36 (s,carboxamide 3H), 1.08 (d, J = 6.02 Hz, 6H). 3-isopropoxy-N-[[2-methyl-4-I-273 1H NMR (400 MHz, DMSO-d6) δ ppm 491.2 [6-(5,6,7,8-tetrahydro-4H-10.13 (br. s., 1H), 8.99 (br. s., 1H), 8.67pyrazolo[1,5-a][1,4]diazepin- (s, 1H), 7.71-7.83 (m, 2H), 7.34 (d, J =2-ylamino)pyrimidin-4- 7.78 Hz, 1H), 6.85 (t, J = 5.77 Hz, 1H),yl]phenyl]methyl]azetidine-1- 4.28-4.50 (m, 5H), 4.22 (d, J = 5.52carboxamide Hz, 2H), 3.98-4.09 (m, 2H), 3.52- 3.68 (m, 3H), 3.41 (br.s., 2H), 2.36 (s, 3H), 2.02 (br. s., 2H), 1.08 (d, J = 6.02 Hz, 6H).N-[[4-[6-[[5-(2- I-274 1H NMR (400 MHz, DMSO-d6) δ ppm 535.2hydroxyethyl)-4,6,7,8- 10.38 (br. s., 1H), 8.72 (s, 1H), 7.67-tetrahydropyrazolo[1,5- 7.85 (m, 2H), 7.36 (d, J = 8.28 Hz, 1H),a][1,4]diazepin-2- 6.69-6.97 (m, 2H), 4.50-4.79 (m,yl]amino]pyrimidin-4-yl]-2- 2H), 4.27-4.47 (m, 3H), 4.22 (d, J =methyl-phenyl]methyl]-3- 5.52 Hz, 2H), 3.99-4.09 (m, 2H), 3.75isopropoxy-azetidine-1- (br. s., 2H), 3.52-3.68 (m, 5H), 3.03-carboxamide 3.22 (m, 2H), 2.36 (s, 3H), 1.99-2.25 (m, 2H), 1.08 (d, J =6.27 Hz, 6H). 3-tert-butyl-N-[[2-methyl-4- I-275 1H NMR (400 MHz,DMSO-d6) δ ppm 503.3 [6-[(5-methyl-6,7-dihydro- 10.45 (br. s., 1H), 8.74(s, 1H), 7.50- 4H-pyrazolo[1,5-a]pyrazin-2- 7.86 (m, 3H), 7.39 (d, J =7.78 Hz, 1H), yl)amino]pyrimidin-4- 6.42-6.70 (m, 2H), 4.14-4.42 (m,yl]phenyl]methyl]pyrrolidine- 4H), 3.80 (br. s., 2H), 3.29-3.54 (m,1-carboxamide 2H), 3.16 (dt, J = 6.53, 10.29 Hz, 2H), 2.88-3.05 (m, 4H),2.54 (s, 1H), 2.37 (s, 3H), 1.93-2.08 (m, 1H), 1.71-1.90 (m, 1H),1.48-1.67 (m, 1H), 0.87- 0.92 (m, 9H). 2-tert-butyl-N-[[4-[6-(6,7- I-2761H NMR (400 MHz, DMSO-d6) δ ppm 504.2 dihydro-4H-pyrazolo[5,1- 10.74(br. s., 1H), 9.13 (t, J = 5.77 Hz, c][1,4]oxazin-2- 1H), 8.79 (s, 1H),8.33 (s, 1H), 7.53- ylamino)pyrimidin-4-yl]-2- 7.84 (m, 3H), 7.43 (d, J= 8.03 Hz, 1H), methyl- 6.31 (br. s., 1H), 4.79 (s, 2H), 4.50 (d, J =phenyl]methyl]thiazole-5- 5.77 Hz, 2H), 4.07 (s, 4H), 2.42 (s,carboxamide 3H), 1.39 (s, 9H). N-[[4-[6-(6,7-dihydro-4H- I-277 1H NMR(400 MHz, DMSO-d6) δ ppm 478.2 pyrazolo[5,1-c][1,4]oxazin-2- 10.80 (br.s., 1H), 8.80 (s, 1H), 7.66- ylamino)pyrimidin-4-yl]-2- 7.80 (m, 2H),7.39 (d, J = 8.53 Hz, 1H), methyl-phenyl]methyl]-3- 6.88 (t, J = 5.65Hz, 1H), 6.31 (br. s., isopropoxy-azetidine-1- 1H), 4.79 (s, 2H),4.28-4.37 (m, 1H), carboxamide 4.23 (d, J = 5.52 Hz, 2H), 3.99-4.13 (m,6H), 3.52-3.69 (m, 3H), 2.37 (s, 3H), 1.08 (d, J = 6.02 Hz, 6H).2-tert-butyl-N-[[2-methyl-4- I-278 1H NMR (400 MHz, METHANOL-d4) 531.2[6-[(5-methyl-4-oxo-6,7- δ ppm 9.10 (t, J = 5.40 Hz, 1H), 8.83 (s,dihydropyrazolo[1,5- 1H), 8.23 (s, 1H), 7.66-7.81 (m, 3H), a]pyrazine-2-7.54 (d, J = 8.03 Hz, 1H), 7.02-7.17 yl)amino]pyrimidin-4- (m, 1H), 4.64(s, 2H), 4.41 (t, J = 6.27 yl]phenyl]methyl]thiazole-5- Hz, 2H), 3.88(t, J = 6.27 Hz, 2H), 3.15 carboxamide (s, 3H), 2.51 (s, 3H), 1.46 (s,9H). 2-tert-butyl-N-[[4-[6-[(5,6- I-279 1H NMR (400 MHz, METHANOL-d4)531.1 dimethyl-6,7-dihydro-4H- δ ppm 9.11 (t, J = 5.65 Hz, 1H), 8.81 (s,pyrazolo[1,5-a]pyrazin-2- 1H), 8.23 (s, 1H), 7.66-7.82 (m, 2H),yl)amino]pyrimidin-4-yl]-2- 7.54 (d, J = 8.03 Hz, 1H), 6.62 (br. s.,methyl- 1H), 4.70-4.80 (m, 1H), 4.52-4.69 phenyl]methyl]thiazole-5- (m,4H), 4.03-4.30 (m, 2H), 3.05 (s, carboxamide 3H), 2.51 (s, 3H), 1.56 (d,J = 6.53 Hz, 3H), 1.46 (s, 9H). 1-tert-butyl-N-[[4-[6-[(5,6- I-280 1HNMR (400 MHz, METHANOL-d4) 514.2 dimethyl-6,7-dihydro-4H- δ ppm 8.80 (s,1H), 8.27 (s, 1H), 7.96 pyrazolo[1,5-a]pyrazin-2- (s, 1H), 7.63-7.82 (m,3H), 7.52 (d, J = yl)amino]pyrimidin-4-yl]-2- 8.03 Hz, 1H), 6.61 (br.s., 1H), 4.69- methyl- 4.79 (m, 1H), 4.51-4.64 (m, 4H), 4.03-phenyl]methyl]pyrazole-4- 4.26 (m, 2H), 3.04 (s, 3H), 2.51 (s,carboxamide 3H), 1.61 (s, 9H), 1.56 (d, J = 6.53 Hz, 3H).3-tert-butyl-N-[[2-methyl-4- I-281 1H NMR (400 MHz, METHANOL-d4) 517.2[6-[(5-methyl-6-oxo-4,7- δ ppm 8.69 (s, 1H), 7.53-7.75 (m, 3H),dihydropyrazolo[1,5- 7.43 (d, J = 7.78 Hz, 1H), 4.71 (s, 3H),a]pyrazine-2- 4.60 (s, 2H), 4.25-4.42 (m, 2H), 3.44-yl)amino]pyrimidin-4- 3.52 (m, 1H), 3.34-3.42 (m, 1H), 3.04-yl]phenyl]methyl]pyrrolidine- 3.06 (m, 3H), 2.37 (s, 3H), 1.94-2.101-carboxamide (m, 1H), 1.77-1.91 (m, 1H), 1.53- 1.71 (m, 1H), 0.81-0.93(m, 9H). 1-tert-butyl-N-[[4-[6-[(4,5- I-282 1H NMR (400 MHz,METHANOL-d4) 514.2 dimethyl-6,7-dihydro-4H- δ ppm 8.81 (s, 1H), 8.27 (s,1H), 7.96 pyrazolo[1,5-a]pyrazin-2- (s, 1H), 7.57-7.84 (m, 3H), 7.52 (d,J = yl)amino]pyrimidin-4-yl]-2- 8.03 Hz, 1H), 6.67 (br. s., 1H), 4.75(q, methyl- J = 6.53 Hz, 1H), 4.61 (s, 2H), 4.36-phenyl]methyl]pyrazole-4- 4.58 (m, 2H), 4.01 (td, J = 4.08, 12.93carboxamide Hz, 1H), 3.82-3.94 (m, 1H), 3.09 (s, 3H), 2.51 (s, 3H), 1.79(d, J = 6.78 Hz, 3H), 1.61 (s, 9H). 2-tert-butyl-N-[[4-[6-[(4,5- I-2831H NMR (400 MHz, METHANOL-d4) 531.2 dimethyl-6,7-dihydro-4H- δ ppm8.79-8.90 (m, 1H), 8.24 (s, 1H), pyrazolo[1,5-a]pyrazin-2- 7.61-7.95 (m,3H), 7.50-7.59 (m, yl)amino]pyrimidin-4-yl]-2- 1H), 6.55-6.78 (m, 1H),4.71-4.83 methyl- (m, 1H), 4.63 (s, 2H), 4.38-4.58 (m,phenyl]methyl]thiazole-5- 2H), 3.97-4.09 (m, 1H), 3.80-3.97 carboxamide(m, 1H), 3.10 (s, 3H), 2.51 (s, 3H), 1.80 (d, J = 6.78 Hz, 3H), 1.46 (s,9H). 3-tert-butyl-N-[[4-[6-[(4,5- I-284 1H NMR (400 MHz, METHANOL-d4)517.3 dimethyl-6,7-dihydro-4H- δ ppm 8.84 (s, 1H), 7.62-8.45 (m, 3H),pyrazolo[1,5-a]pyrazin-2- 7.53 (d, J = 7.78 Hz, 1H), 6.70 (br. s.,yl)amino]pyrimidin-4-yl]-2- 1H), 4.79 (q, J = 6.53 Hz, 1H), 4.43 (d,methyl- J = 5.77 Hz, 4H), 3.98-4.10 (m, 1H),phenyl]methyl]pyrrolidine-1- 3.80-3.98 (m, 1H), 3.42-3.65 (m,carboxamide 2H), 3.11 (s, 4H), 2.34-2.53 (m, 3H), 2.04-2.22 (m, 1H),1.94 (td, J = 6.18, 11.98 Hz, 1H), 1.60-1.86 (m, 5H), 0.94 (br. s., 9H).2-tert-butyl-N-[[4-[6-[[5-(2- I-285 1H NMR (400 MHz, DMSO-d6) δ ppm561.4 hydroxyethyl)-4,6,7,8- 10.35 (br. s., 1H), 9.12 (t, J = 5.65 Hz,tetrahydropyrazolo[1,5- 1H), 8.67-8.77 (m, 1H), 8.33 (s, 1H),a][1,4]diazepin-2- 7.70-7.87 (m, 2H), 7.40 (d, J = 8.03yl]amino]pyrimidin-4-yl]-2- Hz, 1H), 4.32-4.79 (m, 6H), 3.49- methyl-3.84 (m, 3H), 3.01-3.20 (m, 2H), 2.41 phenyl]methyl]thiazole-5- (s, 3H),2.08 (br. s., 2H), 1.39 (s, 9H). carboxamide2-tert-butyl-N-[[2-methyl-4- I-286 1H NMR (400 MHz, DMSO-d6) δ ppm 531.1[6-[(5-methyl-6-oxo-4,7- 11.14 (br. s., 1H), 9.19 (t, J = 5.40 Hz,dihydropyrazolo[1,5- 1H), 8.85 (s, 1H), 8.36 (s, 1H), 7.69- a]pyrazin-2-7.85 (m, 2H), 7.45 (d, J = 8.03 Hz, 1H), yl)amino]pyrimidin-4- 6.46 (br.s., 1H), 4.75 (s, 2H), 4.64 (s, yl]phenyl]methyl]thiazole-5- 2H), 4.51(d, J = 5.52 Hz, 2H), 3.01 (s, carboxamide 3H), 2.43 (s, 3H), 1.39 (s,9H). 3-tert-butoxy-N-[[4-[6-(6,7- I-287 1H NMR (400 MHz, DMSO-d6) δ ppm492.2 dihydro-4H-pyrazolo[5,1- 10.70 (br. s., 1H), 8.78 (s, 1H), 7.48-c][1,4]oxazin-2- 8.01 (m, 3H), 7.38 (d, J = 8.53 Hz, 1H),ylamino)pyrimidin-4-yl]-2- 6.86 (t, J = 5.77 Hz, 1H), 6.30 (br. s.,methyl- 1H), 4.79 (s, 2H), 4.43-4.53 (m, 1H), phenyl]methyl]azetidine-1-4.23 (d, J = 5.52 Hz, 2H), 3.98-4.13 carboxamide (m, 6H), 3.60 (dd, J =4.89, 8.66 Hz, 2H), 2.37 (s, 3H), 1.12 (s, 9H).3-tert-butyl-N-[[4-[6-(6,7- I-288 1H NMR (400 MHz, METHANOL-d4) 490.1dihydro-4H-pyrazolo[5,1- δ ppm 8.78 (s, 1H), 7.62-8.27 (m, 3H),c][1,4]oxazin-2- 7.53 (d, J = 8.03 Hz, 1H), 6.30 (br. s.,ylamino)pyrimidin-4-yl]-2- 1H), 4.84 (s, 2H), 4.34-4.53 (m, 2H), methyl-4.15 (s, 4H), 3.42-3.64 (m, 2H), 3.11 phenyl]methyl]pyrrolidine-1- (t, J= 10.16 Hz, 1H), 2.47 (s, 3H), 2.04- carboxamide 2.22 (m, 1H), 1.94 (td,J = 6.18, 11.98 Hz, 1H), 1.58-1.82 (m, 1H), 0.97 (s, 9H).2-tert-butyl-5-[[2-methyl-4- I-289 ¹H NMR (400 MHz, CD₃OD) δ ppm: 557.2[2-[[1-(1-methyl-4- 8.25 (d, J = 5.2 Hz, 1H), 7.98 (s, 1H),piperidyl)pyrazol-4- 7.88 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H),yl]amino]pyrimidin-4- 7.55 (s, 1H), 7.21 (d, J = 7.6 Hz, 1H),yl]phenyl]methyl]-4H- 7.08 (d, J = 5.2 Hz, 1H), 4.75 (s, 2H),pyrrolo[3,4-d]thiazol-6-one 4.24 (s, 2H), 4.09-4.01 (m, 1H), 2.92- 2.89(m, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 2.20-2.15 (m, 2H), 2.06-1.95 (m,4H), 1.37 (s, 9H). 3-isopropoxy-N-[[4-[2-[(1- I-290 ¹H NMR (400 MHz,CDCl₃) δ: 8.48 (d, 490.2 methylpyrazol-4- J = 5.2 Hz, 1H), 8.38 (s, 1H),8.14 (d, J = yl)amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H), 7.93 (s, 1H), 7.76(d, J = (trifluoromethyl)phenyl]methyl]azetidine- 8.0 Hz, 1H), 7.53 (s,1H), 7.10 (d, J = 1-carboxamide 5.2 Hz, 1H), 6.96 (s, 1H), 4.63 (d, J =5.6 Hz, 2H), 4.54-4.52 (m, 1H), 4.37- 4.34 (m, 1H), 4.14-4.12 (m, 2H),3.93 (s, 3H), 3.88-3.37 (m, 2H), 3.62-3.59 (m, 1H), 1.15 (d, J = 6.0 Hz,6H). 1-tert-butyl-N-[[2-chloro-4- I-291 ¹H NMR (400 MHz, CD₃OD) δ: 8.61(t, 465.2 [2-[(1-methylpyrazol-4- J = 5.6 Hz, 1H), 8.31-8.29 (m, 1H),yl)amino]pyrimidin-4- 8.18 (s, 1H), 8.07 (s, 1H), 7.91-7.88 (m,yl]phenyl]methyl]pyrazole-4- 2H), 7.83 (s, 1H), 7.51 (s, 1H), 7.41 (d,carboxamide J = 8.0 Hz, 1H), 7.08-7.06 (m, 1H), 4.56 (s, 2H), 3.77 (s,3H), 1.49 (s, 9H). 4-[4-[[4-[4-[[(1-tert- I-292 ¹H NMR (400 MHz, CD₃OD)δ: 8.36- 557.3 butylpyrazole-4- 8.34 (m, 1H), 8.21 (s, 1H), 8.09 (s,1H), carbonyl)amino]methyl]-3- 8.00-7.99 (m, 1H), 7.95-7.93 (m, 2H),methyl-phenyl]pyrimidin-2- 7.69 (s, 1H), 7.54-7.50 (m, 1H), 7.26 (d,yl]amino]pyrazol-1- J = 6.0 Hz, 1H), 4.62 (s, 2H), 4.24-4.18yl]cyclohexanecarboxylic (m, 1H), 2.72-2.71 (m, 1H), 2.50 (s, acid 3H),2.31-2.27 (m, 2H), 2.10-2.02 (m, 4H), 1.81-1.73 (m, 2H), 1.63 (s, 9H).3-tert-butyl-N-[[4-[2-[(1- I-293 ¹H NMR (400 MHz, CD₃OD) δ: 8.49 (s,530.3 isopropylpyrazol-4- 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.24 (d, J =yl)amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J =(trifluoromethyl)phenyl]methyl]pyrrolidine- 8.0 Hz, 1H), 7.62 (s, 1H),7.23-7.21 (d, 1-carboxamide J = 5.2 Hz, 1H), 4.65-4.64 (m, 2H),4.52-4.45 (m, 1H), 3.62-3.47 (m, 2H), 3.29-3.27 (m, 1H), 3.13-3.10 (m,1H), 2.11-2.10 (m, 1H), 1.95-1.89 (m, 1H), 1.74-1.69 (m, 1H), 1.50 (d, J= 6.4 Hz, 6H), 0.95 (s, 9H). 3-tert-butoxy-N-[[4-[2-[(1- I-294 ¹H NMR(400 MHz, CD₃OD) δ: 8.53 (s, 530.2 cyclopropylpyrazol-4- 1H), 8.48 (d, J= 5.2 Hz, 1H), 8.31 (d, J = yl)amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H),8.06 (s, 1H), 7.69 (d, J = (trifluoromethyl)phenyl]methyl]azetidine- 8.4Hz, 1H), 7.61 (s, 1H), 7.28 (d, J = 1-carboxamide 5.2 Hz, 1H), 4.64-4.60(m, 3H), 4.22- 4.18 (m, 2H), 3.84-3.80 (m, 2H), 3.66- 3.60 (m, 1H), 1.21(s, 9H), 1.10-1.05 (m, 4H). 3-tert-butyl-N-[[4-[2-[[1-(2- I-295 ¹H NMR(400 MHz, CD₃OD) δ: 8.44 (s, 546.2 methoxyethyl)pyrazol-4- 1H), 8.44 (d,J = 5.2 Hz, 1H), 8.25 (d, J = yl]amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H),8.02 (s, 1H), 7.68-7.64 (trifluoromethyl)phenyl]methyl]pyrrolidine- (m,2H), 7.20 (d, J = 5.2 Hz, 1H), 4.65- 1-carboxamide 4.63 (m, 2H), 4.26(t, J = 5.2 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.68-3.57 (m, 2H), 3.35(s, 3H), 3.27-3.20 (m, 1H), 3.14-3.10 (m, 1H), 2.13-2.10 (m, 1H),1.93-1.91 (m, 1H), 1.73-1.68 (m, 1H), 0.95 (s, 9H).3-tert-butyl-N-[[4-[2-[(1- I-296 ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (s,528.3 cyclopropylpyrazol-4- 1H), 8.33 (d, J = 4.8 Hz, 1H), 8.15 (d, J =yl)amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H), 7.94 (s, 1H), 7.59 (d, J =(trifluoromethyl)phenyl]methyl]pyrrolidine- 8.4 Hz, 1H), 7.50 (s, 1H),7.13 (d, J = 1-carboxamide 5.2 Hz, 1H), 4.56-4.55 (m, 2H), 3.55- 3.49(m, 2H), 3.43-3.39 (m, 1H), 3.06- 3.01 (m, 1H), 2.04-2.03 (m, 1H), 1.85-1.81 (m, 1H), 1.66-1.61 (m, 1H), 1.02- 0.92 (m, 5H), 0.87 (s, 9H).3-tert-butyl-N-[[4-[2-[(1- I-297 ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s,516.3 ethylpyrazol-4- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.21 (d, J =yl)amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H), 7.93 (s, 1H), 7.60 (d, J =(trifluoromethyl)phenyl]methyl]pyrrolidine- 8.4 Hz, 1H), 7.53 (s, 1H),7.18 (d, J = 1-carboxamide 5.2 Hz, 1H), 4.63-4.47 (m, 2H), 4.08 (q, J =7.4 Hz, 2H), 3.54-3.44 (m, 1H), 3.44-3.34 (m, 1H), 3.27-3.22 (m, 1H),3.04-3.02 (m, 1H), 2.12-1.98 (m, 1H), 1.91-1.77 (m, 1H), 1.71-1.58 (m,1H), 1.38 (t, J = 7.4 Hz, 3H), 0.88 (s, 9H).3-tert-butyl-N-[[4-[2-[[1-(1- I-298 ¹H NMR (400 MHz, CD₃OD) δ: 8.39 (s,585.3 methyl-4-piperidyl)pyrazol-4- 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.18(d, J = yl]amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 7.96 (s, 1H), 7.62-7.57(trifluoromethyl)phenyl]methyl]pyrrolidine- (m, 2H), 7.14 (d, J = 5.2Hz, 1H), 4.57- 1-carboxamide 4.52 (m, 2H), 4.07-4.01 (m, 1H), 3.54- 3.51(m, 1H), 3.43-3.40 (m, 1H), 3.22- 3.10 (m, 1H), 3.05-3.02 (m, 1H), 2.92-2.89 (m, 2H), 2.25 (s, 3H), 2.18-1.82 (m, 8H), 1.67-1.62 (m, 1H), 0.88(s, 9H). 3-isopropoxy-N-[[4-[2-[(1- I-299 ¹H NMR (400 MHz, CD₃OD) δ:8.42 (s, 518.2 isopropylpyrazol-4- 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.21(d, J = yl)amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 7.95 (s, 1H), 7.59 (d,J = (trifluoromethyl)phenyl]methyl]azetidine- 8.4 Hz, 1H), 7.53 (s, 1H),7.18 (d, J = 1-carboxamide 5.2 Hz, 1H), 4.50 (s, 2H), 4.46-4.30 (m, 2H),4.18-4.02 (m, 2H), 3.79-3.67 (m, 2H), 3.65-3.49 (m, 1H), 1.42 (d, J =6.8 Hz, 6H), 1.07 (d, J = 6.2 Hz, 6H). 3-methoxy-N-[[2-methyl-4- I-3001H NMR (400 MHz, METHANOL-d4) 408 [2-[(1-methylpyrazol-4- δ: 8.33 (d, J= 6.02 Hz, 1H), 8.00 (d, J = yl)amino]pyrimidin-4- 17.88 Hz, 3H), 7.69(s, 1H), 7.35- yl]phenyl]methyl]azetidine-1- 7.52 (m, 2H), 4.41 (s, 2H),4.26 (s, 1H), carboxamideacid 4.09-4.19 (m, 2H), 3.91-3.99 (m, 3H), 3.83(dd, J = 3.89, 9.73 Hz, 2H), 2.45 (s, 3H) N-[[4-[2-[[1-(2- I-301 ¹H NMR(400 MHz, CD₃OD) δ: 8.43 (s, 520.2 hydroxyethyl)pyrazol-4- 1H), 8.40 (d,J = 5.2 Hz, 1H), 8.25 (d, J = yl]amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H),8.02 (s, 1H), 7.65-7.63 (trifluoromethyl)phenyl]methyl]- (m, 2H), 7.19(d, J = 5.2 Hz, 1H), 4.58 3-isopropoxy-azetidine-1- (s, 2H), 4.46-4.38(m, 1H), 4.25-4.13 carboxamide (m, 4H), 3.91 (t, J = 5.4 Hz, 2H), 3.88-3.81 (m, 2H), 3.70-3.60 (m, 1H), 1.16 (d, J = 6.4 Hz, 6H).3-tert-butoxy-N-[[2-methyl-4- I-302 ¹H NMR (400 MHz, CD₃OD) δ: 8.39533.3 [2-[[1-(1-methyl-4- (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.95piperidyl)pyrazol-4- (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.68yl]amino]pyrimidin-4- (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20yl]phenyl]methyl]azetidine-1- (d, J = 5.2 Hz, 1H), 4.61-4.56 (m, 1H),carboxamide 4.39 (s, 2H), 4.21-4.13 (m, 3H), 3.80- 3.77 (m, 2H),3.04-3.01 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.30-2.24 (m, 2H),2.19-2.04 (m, 4H), 1.20 (s, 9H). 3-tert-butyl-N-[[4-[2-[[1-(2- I-303 ¹HNMR (400 MHz, CD₃OD) δ: 8.28 492.3 methoxyethyl)pyrazol-4- (d, J = 4.8Hz, 1H), 7.99 (s, 1H), 7.83 yl]amino]pyrimidin-4-yl]-2- (d, J = 6.8 Hz,1H), 7.58 (s, 1H), 7.30 methyl- (d, J = 8.4 Hz, 1H), 7.08 (d, J = 5.2Hz, phenyl]methyl]pyrrolidine-1- 1H), 6.56 (s, 1H), 4.38-4.28 (m, 2H),carboxamide 4.19 (t, J = 4.8 Hz, 2H), 3.66 (t, J = 5.2 Hz, 2H),3.51-3.46 (m, 1H), 3.40-3.36 (m, 1H), 3.25 (s, 3H), 3.20-3.18 (m, 1H),3.02-2.99 (m, 1H), 2.34 (s, 3H), 2.01-2.00 (m, 1H), 1.84-1.81 (m, 1H),1.64-1.59 (m, 1H), 0.87 (s, 9H). 3-tert-butoxy-N-[[4-[2-[[1-(2- I-304 ¹HNMR (400 MHz, CD₃OD) δ: 8.39 494.3 methoxyethyl)pyrazol-4- (d, J = 5.2Hz, 1H), 8.09 (s, 1H), 7.96- yl]amino]pyrimidin-4-yl]-2- 7.95 (m, 2H),7.67 (s, 1H), 7.39 (d, J = methyl- 8.4 Hz, 1H), 7.22 (d, J = 4.8 Hz,1H), phenyl]methyl]azetidine-1- 4.61-4.56 (m, 1H), 4.39 (s, 2H), 4.30(t, carboxamide J = 5.2 Hz, 2H), 4.19-4.15 (m, 2H), 3.80-3.75 (m, 4H),3.35 (s, 3H), 2.44 (s, 3H), 1.20 (s, 9H). 3-tert-butyl-N-[[4-[2-[(1-I-305 ¹H NMR (400 MHz, CD₃OD) δ: 8.28 462.3 ethylpyrazol-4- (d, J = 5.6Hz, 1H), 7.92 (s, 1H), 7.82 yl)amino]pyrimidin-4-yl]-2- (d, J = 7.2 Hz,1H), 7.56 (s, 1H), 7.30 methyl- (d, J = 8.4 Hz, 1H), 7.09 (d, J = 5.2Hz, phenyl]methyl]pyrrolidine-1- 1H), 4.37-4.28 (m, 2H), 4.06 (q, J =7.2 carboxamide Hz, 2H), 3.49-3.47 (m, 1H), 3.39-3.37 (m, 1H), 3.19-3.16(m, 1H), 3.04-2.98 (m, 1H), 2.33 (s, 3H), 2.04-1.99 (m, 1H), 1.86-1.80(m, 1H), 1.64-1.59 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H).3-tert-butoxy-N-[[4-[2-[(1- I-306 ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s,532.3 isopropylpyrazol-4- 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.21 (d, Jyl)amino]pyrimidin-4-yl]-2- = 8.0 Hz, 1H), 7.95 (s, 1H), 7.60 (d, J =methyl- 8.4 Hz, 1H), 7.53 (s, 1H), 7.17 (d, J =phenyl]methyl]azetidine-1- 4.8 Hz, 1H), 4.53-4.47 (m, 1H), 4.49 (s,carboxamide 2H), 4.44-4.37 (m, 1H), 4.11-4.08 (m, 2H), 3.73-3.69 (m,2H), 1.42 (d, J = 6.4 Hz, 3H), 1.10 (s, 9H). 3-(2-fluoroethoxy)-N-[[2-I-307 ¹H NMR (400 MHz, CD₃OD) δ: 8.28- 440.2 methyl-4-[2-[(1- 8.26 (m,1H), 7.86 (s, 1H), 7.82-7.81 methylpyrazol-4- (m, 2H), 7.53 (s, 1H),7.28 (d, J = 8.0 yl)amino]pyrimidin-4- Hz, 1H), 7.08-7.06 (m, 1H), 4.49(t, J = yl]phenyl]methyl]azetidine-1- 4.0 Hz, 1H), 4.37 (t, J = 4.0 Hz,1H), carboxamide 4.32-4.26 (m, 1H), 4.27 (s, 2H), 4.08- 4.05 (m, 2H),3.78 (s, 3H), 3.76-3.74 (m, 2H), 3.62 (t, J = 4.0 Hz, 1H), 3.54 (t, J =4.0 Hz, 1H), 2.31 (s, 3H). 3-tert-butyl-N-[[4-[2-[(1- I-308 ¹H NMR (400MHz, CD₃OD) δ: 8.33 474.3 cyclopropylpyrazol-4- (d, J = 5.2 Hz, 1H),8.03 (s, 1H), 7.89- yl)amino]pyrimidin-4-yl]-2- 7.85 (m, 2H), 7.61 (s,1H), 7.37 (d, J = methyl- 8.0 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H),phenyl]methyl]pyrrolidine-1- 4.45-4.35 (m, 2H), 3.63-3.54 (m, 2H),carboxamide 3.48-3.43 (m, 1H), 3.28-3.23 (m, 1H), 3.08 (t, J = 10.0 Hz,1H), 2.40 (s, 3H), 2.07-2.05 (m, 1H), 1.92-1.85 (m, 1H), 1.71-1.65 (m,1H), 1.10-1.02 (m, 4H), 0.93 (s, 9H). 1-tert-butyl-5-[[2-methyl-4- I-309¹H NMR (400 MHz, CD₃OD) δ: 8.56 526.3 [6-[(5-methyl-6,7-dihydro- (d, J =1.2 Hz, 1H), 7.77-7.72 (m, 3H), 4H-pyrazolo[1,5-a]pyrazin-2- 7.51 (s,1H), 7.31 (d, J = 7.6 Hz, 1H), yl)amino]pyrimidin-4- 6.23 (s, 1H), 4.75(s, 2H), 4.10 (t, J = yl]phenyl]methyl]-6,7- 5.2 Hz, 2H), 3.69 (s, 2H),3.55 (t, J = dihydropyrazolo[4,3- 7.2 Hz, 2H), 3.21 (t, J = 6.8 Hz, 2H),c]pyridin-4-one 2.99 (t, J = 5.6 Hz, 2H), 2.50 (s, 3H), 2.38 (s, 3H),1.60 (s, 9H). 1-[[4-[2-[[1-(2- I-310 ¹H NMR (400 MHz, CD₃OD) δ: 8.59 (s,518.2 hydroxyethyl)pyrazol-4- 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.40 (d, J= yl]amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 8.05 (s, 1H), 7.71-7.64(trifluoromethyl)phenyl]methyl]- (m, 2H), 7.36 (d, J = 5.2 Hz, 1H), 4.974-isobutyl-piperazin-2-one (s, 2H), 4.23 (t, J = 5.6 Hz, 2H), 4.10 (s,2H), 3.91 (t, J = 5.6 Hz, 2H), 3.68 (brs, 4H), 3.16 (d, J = 7.6 Hz, 2H),2.26-2.19 (m, 1H), 1.09 (d, J = 6.8 Hz, 6H).3-tert-butyl-N-[[4-[2-[[1-(1- I-311 ¹H NMR (400 MHz, CD₃OD) δ: 8.36-557.3 methylazetidin-3-yl)pyrazol- 8.33 (m, 2H), 8.18 (d, J = 8.4 Hz,1H), 4-yl]amino]pyrimidin-4-yl]-2- 8.02 (s, 1H), 7.64 (s, 1H), 7.58 (d,J = (trifluoromethyl)phenyl]methyl]pyrrolidine- 8.8 Hz, 1H), 7.14 (d, J= 4.8 Hz, 1H), 1-carboxamide 5.00-4.95 (m, 1H), 4.58-4.49 (m, 2H),4.07-4.03 (m, 2H), 3.84-3.80 (m, 2H), 3.51-3.47 (m, 1H), 3.41-3.37 (m,1H), 3.24-3.22 (m, 1H), 3.03-3.00 (m, 1H), 2.58 (s, 3H), 2.05-2.00 (m,1H), 1.84- 1.80 (m, 1H), 1.64-1.59 (m, 1H), 0.86 (s, 9H).N-[[4-[2-[[1-[1,1-dimethyl-2- I-312 ¹H NMR (400 MHz, CD₃OD) δ: 8.28589.3 oxo-2-(2,2,2- (d, J = 4.8 Hz, 1H), 8.17 (br, 1H), 7.85trifluoroethylamino)ethyl]pyrazol- (s, 1H), 7.82 (d, J = 8.0 Hz, 1H),7.64 4-yl]amino]pyrimidin-4- (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.10-yl]-2-methyl-phenyl]methyl]- 7.09 (m, 1H), 4.32-4.29 (m, 1H), 4.293-isopropoxy-azetidine-1- (s, 2H), 4.08-4.05 (m, 2H), 3.77 (q, J =carboxamide 9.2 Hz, 2H), 3.71-3.68 (m, 2H), 3.58- 3.52 (m, 1H), 2.31 (s,3H), 1.74 (s, 6H), 1.06 (d, J = 6.0 Hz, 6H). 3-isopropoxy-N-[[4-[2-[[1-I-313 ¹H NMR (400 MHz, CD₃OD): 8.37 (d, 546.2 [(3S)-tetrahydrofuran-3- J= 5.2 Hz, 1H), 8.23-8.21 (m, 2H), yl]pyrazol-4- 8.01 (s, 1H), 7.61-7.56(m, 2H), 7.17 (d, yl]amino]pyrimidin-4-yl]-2- J = 5.2 Hz, 1H), 4.95-4.90(m, 1H), (trifluoromethyl)phenyl]methyl]azetidine- 4.52 (s, 2H),4.38-4.34 (m, 1H), 4.15- 1-carboxamide 4.02 (m, 3H), 3.98-3.93 (m, 2H),3.87- 3.75 (m, 3H), 3.62-3.56 (m, 1H), 2.45- 2.38 (m, 1H), 2.27-2.20 (m,1H), 1.09 (d, J = 6.4 Hz, 1H). 3-isopropoxy-N-[[4-[2-[[1- I-314 ¹H NMR(400 MHz, CDCl₃) δ: 8.48 (d, 546.2 [(3R)-tetrahydrofuran-3- J = 5.2 Hz,1H), 8.36 (s, 1H), 8.14 (d, J = yl]pyrazol-4- 8.0 Hz, 1H), 8.04 (s, 1H),7.75 (d, J = yl]amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 7.57 (s, 1H), 7.13(s, 1H), (trifluoromethyl)phenyl]methyl]azetidine- 7.10 (d, J = 5.2 Hz,1H), 5.00-4.95 (m, 1-carboxamide 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.55 (t,J = 6.0 Hz, 1H), 4.38-4.32 (m, 1H), 4.19- 4.07 (m, 5H), 3.99-3.93 (m,1H), 3.87- 3.85 (m, 2H), 3.63-3.57 (m, 1H), 2.53- 2.36 (m, 2H), 1.15 (d,J = 6.4 Hz, 6H). 2-tert-butyl-N-[[4-[2-(5,6- I-315 ¹H NMR (400 MHz,CD₃OD) δ: 8.23- 488 dihydro-4H-pyrrolo[1,2- 8.20 (m, 1H), 8.12 (s, 1H),7.82 (s, 1H), b]pyrazol-3- 7.78 (d, J = 6.8 Hz, 1H), 7.56 (s, 1H),ylamino)pyrimidin-4-yl]-2- 7.29 (d, J = 8.0 Hz, 1H), 7.08-7.05 (m,methyl- 1H), 4.49 (s, 2H), 4.01-3.90 (m, 2H), phenyl]methyl]thiazole-5-2.82-2.79 (m, 2H), 2.51-2.48 (m, 2H), carboxamide 2.33 (s, 3H), 1.35 (s,9H). 3-tert-butyl-N-[[4-[2-[[1- I-316 ¹H NMR (400 MHz, CD₃OD) δ: 8.36(s, 557.3 [(3S)-pyrrolidin-3-yl]pyrazol- 1H), 8.32 (d, J = 5.2 Hz, 1H),8.15 (d, J = 4-yl]amino]pyrimidin-4-yl]-2- 8.4 Hz, 1H), 7.94 (s, 1H),7.58-7.56 (trifluoromethyl)phenyl]methyl]pyrrolidine- (m, 2H), 7.11 (d,J = 4.8 Hz, 1H), 4.87- 1-carboxamide 4.82 (m, 1H), 4.56-4.52 (m, 2H),3.51- 3.49 (m, 2H), 3.40-3.38 (m, 1H), 3.31- 3.17 (m, 3H), 3.07-2.99 (m,2H), 2.34- 2.25 (m, 1H), 2.18-2.10 (m, 1H), 2.05- 1.97 (m, 1H),1.85-1.79 (m, 1H), 1.67- 1.56 (m, 1H), 0.85 (s, 9H).3-isopropyl-N-[[4-[2-[[1-(2- I-317 ¹H NMR (400 MHz, CDCl₃) δ: 8.46 (d,523.3 methoxyethyl)pyrazol-4- J = 5.2 Hz, 1H), 8.36 (s, 1H), 8.15 (d, J= yl]amino]pyrimidin-4-yl]-2- 8.0 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J =(trifluoromethyl)phenyl]methyl]pyrrolidine- 8.0 Hz, 1H), 7.60 (s, 1H),7.09 (d, J = 1-carboxamide 5.2 Hz, 1H), 7.01 (s, 1H), 4.69-4.64 (m, 3H),4.30 (t, J = 5.2 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.58-3.50 (m, 2H),3.36 (s, 3H), 2.94-2.89 (m, 1H), 2.92 (t, J = 9.6 Hz, 1H), 2.08-2.02 (m,1H), 1.90- 1.82 (m, 1H), 2.15-1.45 (m, 2H), 0.93- 0.90 (m, 6H).3-tert-butyl-N-[[4-[2-[[1- I-318 ¹H NMR (400 MHz, CD₃OD) δ: 8.39 557.3[(3R)-pyrrolidin-3-yl]pyrazol- (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.194-yl]amino]pyrimidin-4-yl]-2- (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.60-(trifluoromethyl)phenyl]methyl]pyrrolidine- 7.57 (m, 2H), 7.16 (d, J =5.6 Hz, 1H), 1-carboxamide 4.86-4.82 (m, 1H), 4.56-4.52 (m, 2H),3.52-3.48 (m, 1H), 3.42-3.38 (m, 1H), 3.27-3.24 (m, 3H), 3.18-3.17 (m,1H), 3.05-2.96 (m, 2H), 2.31-2.26 (m, 1H), 2.17-2.02 (m, 2H), 1.85-1.81(m, 1H), 1.66-1.61 (m, 1H), 0.87 (s, 9H). 3-tert-butoxy-N-[[2-(2- I-319¹H NMR (400 MHz, CD₃OD) δ: 8.40 494.3. methoxyethyl)-4-[2-[(1- (d, J =5.2 Hz, 1H), 8.02 (d, J = 1.6 Hz, methylpyrazol-4- 1H), 8.00 (s, 1H),7.95 (dd, J = 8.0, 1.6 yl)amino]pyrimidin-4- Hz, 1H), 7.64 (s, 1H), 7.42(d, J = 8.0 yl]phenyl]methyl]azetidine-1- Hz, 1H), 7.21 (d, J = 5.2 Hz,1H), 4.59- carboxamide 4.56 (m, 1H), 4.44 (s, 2H), 4.17-4.13 (m, 2H),3.90 (s, 3H), 3.79-3.76 (m, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.36 (s, 3H),3.04 (t, J = 6.8 Hz, 2H), 1.19 (s, 9H). 3-tert-butyl-N-[[2-(2- I-320 ¹HNMR (400 MHz, CD₃OD) δ: 8.40 492.3 methoxyethyl)-4-[2-[(1- (d, J = 5.2Hz, 1H), 8.02 (s, 1H), 8.00 methylpyrazol-4- (s, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.64 yl)amino]pyrimidin-4- (s, 1H), 7.44 (d, J = 8.0 Hz, 1H),7.21 yl]phenyl]methyl]pyrrolidine- (d, J = 5.2 Hz, 1H), 4.49 (s, 2H),3.90 1-carboxamide (s, 3H), 3.71 (t, J = 6.8 Hz, 2H), 3.59- 3.54 (m,1H), 3.48-3.44 (m, 1H), 3.36 (s, 3H), 3.29-3.25 (m, 1H), 3.12-3.07 (m,1H), 3.06 (t, J = 6.8 Hz, 2H), 2.16- 2.07 (m, 1H), 1.95-1.89 (m, 1H),1.77- 1.69 (m, 1H), 0.96 (s, 9H). 3-tert-butyl-N-[[4-[2-[(1,5- I-321 ¹HNMR (400 MHz, CD₃OD) δ: 8.27 492.3 dimethylpyrazol-4- (d, J = 5.2 Hz,1H), 7.96 (s, 1H), 7.89 yl)amino]pyrimidin-4-yl]-2- (d, J = 8.0 Hz, 1H),7.59 (s, 1H), 7.41 (2- (d, J = 8.0 Hz, 1H), 7.17 (d, J = 5.6 Hz,hydroxyethyl)phenyl]methyl]pyrrolidine- 1H), 4.51-.4.43 (m, 2H),3.85-3.82 (m, 1-carboxamide 2H), 3.79 (s, 3H), 3.56-3.51 (m, 1H),3.45-3.41 (m, 1H), 3.28-3.21 (m, 1H), 3.08-2.97 (m, 3H), 2.21 (s, 3H),2.06- 2.04 (m, 1H), 1.89-1.86 (m, 1H), 1.69- 1.64 (m, 1H), 0.93 (s, 9H).3-tert-butoxy-N-[[4-[2-(5,6- I-322 ¹H NMR (400 MHz, CD₃OD) δ: 8.22 476.2dihydro-4H-pyrrolo[1,2- (d, J = 5.2 Hz, 1H), 7.79-7.77 (m, 2H),b]pyrazol-3- 7.57 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H),ylamino)pyrimidin-4-yl]-2- 7.08 (d, J = 5.6 Hz, 1H), 4.49-4.46 (m,methyl- 1H), 4.26 (s, 2H), 4.08-4.01 (m, 4H), phenyl]methyl]azetidine-1-3.69-3.65 (m, 2H), 2.83 (t, J = 7.2 Hz, carboxamide 2H), 2.56-2.49 (m,2H), 2.30 (s, 3H), 1.00 (s, 9H). 3-tert-butoxy-N-[[4-[2-(5,6- I-323 ¹HNMR (400 MHz, CD₃OD) δ: 8.24 520 dihydro-4H-pyrrolo[1,2- (d, J = 5.2 Hz,1H), 7.87 (s, 1H), 7.81 b]pyrazol-3- (d, J = 8.0 Hz, 1H), 7.57 (s, 1H),7.30 ylamino)pyrimidin-4-yl]-2-(2- (d, J = 7.6 Hz, 1H), 7.09 (d, J = 5.2Hz, methoxyethyl)phenyl]methyl]azetidine- 1H), 4.48-4.45 (m, 1H), 4.33(s, 2H), 1-carboxamide 4.06-4.01 (m, 4H), 3.68-3.65 (m, 2H), 3.57 (t, J= 6.8 Hz, 2H), 3.25 (s, 3H), 2.92 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 7.2Hz, 2H), 2.55-2.51 (m, 2H), 1.09 (s, 9H). 3-tert-butyl-N-[[4-[2-(5,6-I-324 ¹H NMR (400 MHz, CD₃OD) δ: 8.23 504.2 dihydro-4H-pyrrolo[1,2- (d,J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.81 b]pyrazol-3- (d, J = 8.0 Hz, 1H),7.56 (s, 1H), 7.33 ylamino)pyrimidin-4-yl]-2-(2- (d, J = 8.4 Hz, 1H),7.09 (d, J = 5.6 Hz, hydroxyethyl)phenyl]methyl]pyrrolidine- 1H),4.23-4.33 (m, 2H), 4.03 (t, J = 7.2 1-carboxamide Hz, 2H), 3.73 (t, J =7.2 Hz, 2H), 3.45 (t, J = 9.2 Hz, 1H), 3.35 (t, J = 9.2 Hz, 1H),3.18-3.13 (m, 1H), 2.92 (t, J = 10.4 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H),2.83 (t, J = 7.2 Hz, 2H), 2.56-2.49 (m, 2H), 2.01-1.98 (m, 1H),1.84-1.78 (m, 1H), 1.63-1.57 (m, 1H), 0.85 (s, 9H).(3S)-3-tert-butyl-N-[[4-[2- I-325 ¹H NMR (400 MHz, CD₃OD) δ: 8.20 518.3(5,6-dihydro-4H-pyrrolo[1,2- (d, J = 5.2 Hz, 1H), 7.85 (d, J = 1.6 Hz,b]pyrazol-3- 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.57ylamino)pyrimidin-4-yl]-2-(2- (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.05methoxyethyl)phenyl]methyl]pyrrolidine- (d, J = 5.2 Hz, 1H), 4.37-4.35(m, 2H), 1-carboxamide 4.00 (t, J = 7.2 Hz, 2H), 3.55 (t, J = 6.8 Hz,2H), 3.46-3.31 (m, 2H), 3.23 (s, 3H), 3.18-3.12 (m, 1H), 2.99-2.89 (m,3H), 2.82-2.79 (m, 2H), 2.53-2.45 (m, 2H), 1.97-1.95 (m, 1H), 1.80-1.75(m, 1H), 1.60-1.55 (m, 1H), 0.83 (s, 9H). 3-isopropoxy-N-[6-[2-[[1-(1-I-326 1H NMR (400 MHz, CD3OD) δ: 8.39 545.4methyl-4-piperidyl)pyrazol-4- (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.94-yl]amino]pyrimidin-4- 7.86 (m, 2H), 7.67 (s, 1H), 7.41 (d, J =yl]tetralin-1-yl]azetidine-1- 8.0 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H),carboxamide 4.99-4.94 (m, 1H), 4.45-4.34 (m, 1H), 4.20-4.11 (m, 3H),3.82-3.75 (m, 2H), 3.71-3.63 (m, 1H), 3.03-3.00 (m, 2H), 2.95-2.83 (m,2H), 2.35 (s, 3H), 2.30- 2.24 (m, 2H), 2.19-2.14 (m, 2H), 2.13- 1.98 (m,4H), 1.88-1.76 (m, 2H), 1.16 (d, J = 6.4 Hz, 6H).3-tert-butyl-N-[6-[2-[[1-(2- I-327 1H NMR (400 MHz, CD3OD) δ: 8.33 504.3hydroxyethyl)pyrazol-4- (d, J = 5.2 Hz, 1H), 8.07 (s, 1H), 7.89-yl]amino]pyrimidin-4- 7.83 (m, 2H), 7.66 (s, 1H), 7.41 (d, J =yl]tetralin-1-yl]pyrrolidine-1- 8.4 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H),carboxamide 5.04-5.02 (m, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.90 (t, J =5.6 Hz, 2H), 3.56-3.44 (m, 2H), 3.29-3.24 (m, 1H), 3.11-3.04 (m, 1H),2.89-2.86 (m, 2H), 2.09-1.98 (m, 3H), 1.92-1.65 (m, 4H), 0.93 (s, 9H).3-tert-butyl-N-[2-[2-[(1- I-328 1H NMR (400 MHz, CD3OD) δ: 8.25 502.3ethylpyrazol-4- (d, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.81-yl)amino]pyrimidin-4-yl]- 7.76 (m, 2H), 7.55 (s, 1H), 7.29-7.256,7,8,9-tetrahydro-5H- (m, 1H), 7.06 (d, J = 5.6Hz, 1H), 6.49-benzo[7]annulen-5- 6.43 (m, 1H), 5.06-4.99 (m, 1H), 4.05yl]pyrrolidine-1-carboxamide (q, J = 7.2 Hz, 2H), 3.57-3.37 (m, 2H),3.25-3.23 (m, 1H), 3.09-2.79 (m, 3H), 2.02-1.76 (m, 6H), 1.64-1.56 (m,2H), 1.36 (t, J = 7.2 Hz, 3H), 1.27-1.17 (m, 1H), 0.86 (s, 9H).N-[2-formyl-8-[2-[(1- I-329 1H NMR (400 MHz, CD3OD) δ: 8.42- 505.3methylpyrazol-4- 8.40 (m, 1H), 8.21-8.15 (m, 1H), 8.08-yl)amino]pyrimidin-4-yl]- 7.98 (m, 3H), 7.64-7.59 (m, 1H), 7.48-1,3,4,5-tetrahydro-2- 7.43 (m, 1H), 7.23 (d, J = 5.6 Hz, 1H),benzazepin-5-yl]-3- 5.30-5.24 (m, 1H), 5.06-5.02 (m, 1H),isopropoxy-azetidine-1- 4.49-4.32 (m, 2H), 4.29-4.20 (m, 2H),carboxamide 3.93-3.83 (m, 6H), 3.78-3.66 (m, 2H), 2.13-2.05 (m, 1H),1.97-1.88 (m, 1H), 1.19-1.17 (m, 6H). 3-tert-butyl-N-[2-[2-[(1- I-330 1HNMR (400 MHz, CD3OD) δ: 8.27 558.3 tetrahydropyran-4-ylpyrazol- (d, J =5.2 Hz, 1H), 8.02 (s, 1H), 7.81- 4-yl)amino]pyrimidin-4-yl]- 7.79 (m,2H), 7.58 (s, 1H), 7.31-7.27 6,7,8,9-tetrahydro-5H- (m, 1H), 7.07 (d, J= 5.2 Hz, 1H), 5.07- benzo[7]annulen-5- 5.02 (m, 1H), 4.27-4.21 (m, 1H),3.97- yl]pyrrolidine-1-carboxamide 3.94 (m, 2H), 3.59-3.40 (m, 4H),3.28- 3.26 (m, 1H), 3.11-2.80 (m, 3H), 2.07- 1.78 (m, 10H), 1.66-1.58(m, 2H), 1.28- 1.24 (m, 1H), 0.88 (s, 9H). 3-ethoxy-N-[2-[2-[(1- I-3311H NMR (400 MHz, CDCl3) δ: 8.39 462.2 methylpyrazol-4- (d, J = 5.2 Hz,1H), 7.87 (s, 1H), 7.81- yl)amino]pyrimidin-4-yl]- 7.77 (m, 2H), 7.55(s, 1H), 7.36-7.30 6,7,8,9-tetrahydro-5H- (m, 2H), 7.05 (d, J = 5.2 Hz,1H), 5.09 benzo[7]annulen-5- (t, J = 8.0 Hz, 1H), 4.53 (d, J = 8.4 Hz,yl]azetidine-1-carboxamide 1H), 4.34-4.28 (m, 1H), 4.19-4.13 (m, 2H),3.94-3.88 (m, 5H), 3.46 (q, J = 7.2 Hz, 2H), 3.01-2.85 (m, 2H),1.91-1.74 (m, 5H), 1.58-1.51 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H).3-tert-butoxy-N-[2-[6-(6,7- I-332 1H NMR (400 MHz, CDCl3) δ: 8.76 (d,532.3 dihydro-4H-pyrazolo[5,1- J = 0.8 Hz, 1H), 7.80 (d, J = 1.6 Hz,c][1,4]oxazin-2- 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.48ylamino)pyrimidin-4-yl]- (s, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.06,7,8,9-tetrahydro-5H- Hz, 1H), 6.10 (s, 1H), 5.08 (t, J = 8.0benzo[7]annulen-5- Hz, 1H), 4.84 (s, 2H), 4.53-4.42 (m,yl]azetidine-1-carboxamide 2H), 4.20-4.05 (m, 6H), 3.94-3.80 (m, 2H),3.04-2.81 (m, 2H), 2.03-1.72 (m, 5H), 1.61-1.49 (m, 1H), 1.19 (s, 9H).3-isopropoxy-N-[2-[2-[[1- I-333 1H NMR (400 MHz, CD3OD) δ: 8.28 532[(3R)-tetrahydrofuran-3- (d, J = 5.2 Hz, 1H), 8.08 (br, 1H), 7.84-yl]pyrazol-4- 7.81 (m, 1H), 7.79 (s, 1H), 7.53 (d, J =yl]amino]pyrimidin-4-yl]- 2.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H),6,7,8,9-tetrahydro-5H- 7.11 (d, J = 4.8 Hz, 1H), 4.97-4.89 (m,benzo[7]annulen-5- 2H), 4.37-4.32 (m, 1H), 4.17-3.91 (m,yl]azetidine-1-carboxamide 5H), 3.86-3.71 (m, 3H), 3.61-3.55 (m, 1H),2.96-2.89 (m, 2H), 2.46-2.37 (m, 1H), 2.23-2.17 (m, 1H), 1.89-1.78 (m,4H), 1.61-1.56 (m, 1H), 1.28-1.23 (m, 1H), 1.08 (d, J = 6.0 Hz, 6H)3-tert-butoxy-N-[2-[2-[[1- I-334 1H NMR (400 MHz, CD3OD) δ: 8.27 546.3[(3S)-tetrahydrofuran-3- (d, J = 5.2 Hz, 1H), 8.07 (s, 1H), 7.84-yl]pyrazol-4- 7.80 (m, 1H), 7.78 (s, 1H), 7.53 (d, J =yl]amino]pyrimidin-4-yl]- 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H),6,7,8,9-tetrahydro-5H- 7.09 (d, J = 5.6 Hz, 1H), 4.95-4.89 (m,benzo[7]annulen-5- 2H), 4.53-4.47 (m, 1H), 4.16-3.90 (m,yl]azetidine-1-carboxamide 5H), 3.85-3.69 (m, 3H), 2.95-2.84 (m, 2H),2.45-2.36 (m, 1H), 2.22-2.16 (m, 1H), 1.89-1.86 (m, 3H), 1.82-1.76 (m,1H), 1.62-1.52 (m, 1H), 1.30-1.26 (m, 1H), 1.10 (s, 9H).3-isopropoxy-N-[8-[2-[(1- I-335 1H NMR (400 MHz, CDCl3) δ: 8.43 (d, 478methylpyrazol-4- J = 5.2 Hz, 1H), 7.88 (s, 1H), 7.72-7.64yl)amino]pyrimidin-4-yl]- (m, 2H), 7.53 (s, 1H), 7.39 (d, J = 7.82,3,4,5-tetrahydro-1- Hz, 1H), 7.19 (s, 1H), 7.03 (d, J = 5.2benzoxepin-5-yl]azetidine-1- Hz, 1H), 5.21-5.09 (m, 1H), 4.89 (d, J =carboxamide 9.2 Hz, 1H), 4.46-4.26 (m, 2H), 4.15- 4.04 (m, 2H), 3.92 (s,3H), 3.87-3.70 (m, 3H), 3.64-3.51 (m, 1H), 2.32-2.13 (m, 2H), 1.88-1.69(m, 2H), 1.14 (d, J = 5.6 Hz, 6H). N-[2-[2-[[1-(2-hydroxy-2- I-336 1HNMR (400 MHz, CDCl3) δ: 8.40 (d, 534.3 methyl-propyl)pyrazol-4- J = 5.2Hz, 1H), 7.95 (s, 1H), 7.80 (d, J = yl]amino]pyrimidin-4-yl]- 8.0 Hz,1H), 7.76 (s, 1H), 7.60 (s, 6,7,8,9-tetrahydro-5H- 1H), 7.35 (d, J = 8.0Hz, 1H), 7.05 (d, J = benzo[7]annulen-5-yl]-3- 5.2 Hz, 1H), 5.09 (t, J =8.4 Hz, 1H), isopropoxy-azetidine-1- 4.54 (d, J = 7.6 Hz, 1H), 4.48-4.30(m, carboxamide 1H), 4.23-4.10 (m, 2H), 4.05 (s, 2H), 3.99-3.83 (m, 3H),3.68-3.55 (m, 1H), 3.03-2.80 (m, 2H), 1.88-1.69 (m, 5H), 1.64-1.43 (m,1H), 1.21 (s, 6H), 1.17 (d, J = 5.2 Hz, 6H)3-tert-butoxy-N-[2-[2-[[1-(2- I-337 1H NMR (400 MHz, CDCl3) δ: 8.39 (d,548.3 hydroxy-2-methyl- J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J =propyl)pyrazol-4- 8.0 Hz, 1H), 7.75 (s, 1H), 7.59 (s,yl]amino]pyrimidin-4-yl]- 1H), 7.53 (s, 1H), 7.34 (d, J = 8.0 Hz,6,7,8,9-tetrahydro-5H- 1H), 7.05 (d, J = 5.2 Hz, 1H), 5.09 (t, J =benzo[7]annulen-5- 8.4 Hz, 1H), 4.57 (d, J = 7.8 Hz, 1H),yl]azetidine-1-carboxamide 4.54-4.43 (m, 1H), 4.23-4.09 (m, 2H), 4.05(s, 2H), 3.95-3.81 (m, 2H), 3.02- 2.81 (m, 2H), 1.94-1.68 (m, 5H), 1.61-1.43 (m, 1H), 1.20 (s, 6H), 1.19 (s, 9H). 3-isopropoxy-N-[2-[2-[[1-I-338 1H NMR (400 MHz, CD3OD) δ: 8.27 532.3 [(3S)-tetrahydrofuran-3- (d,J = 4.8 Hz, 1H), 8.06 (s, 1H), 7.83- yl]pyrazol-4- 7.78 (m, 2H), 7.53(s, 1H), 7.26 (d, J = yl]amino]pyrimidin-4-yl]- 8.0 Hz, 1H), 7.09 (d, J= 5.2 Hz, 1H), 6,7,8,9-tetrahydro-5H- 4.95-4.89 (m, 2H), 4.37-4.31 (m,1H), benzo[7]annulen-5- 4.16-4.02 (m, 5H), 3.90-3.71 (m, 3H),yl]azetidine-1-carboxamide 4.61-3.55 (m, 1H), 2.94-2.88 (m, 2H),2.45-2.36 (m, 1H), 2.19-2.17 (m, 1H), 1.89-1.76 (m, 4H), 1.60-1.52 (m,1H), 1.31-1.18 (m, 1H), 1.07 (d, J = 6.0 Hz, 6H) 3-methoxy-N-[2-[2-[(1-I-339 1H NMR (400 MHz, CD3OD) δ: 8.27 448 methylpyrazol-4- (d, J = 5.2Hz, 1H), 7.85 (s, 1H), 7.82 yl)amino]pyrimidin-4-yl]- (dd, J = 6.4, 1.6Hz, 1H), 7.77 (d, J = 6,7,8,9-tetrahydro-5H- 1.2 Hz, 1H), 7.55 (s, 1H),7.26 (d, J = benzo[7]annulen-5- 8.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H),yl]azetidine-1-carboxamide 4.94 (d, J = 10.4 Hz, 1H), 4.18-4.06 (m, 3H),3.80-3.73 (m, 5H), 3.23 (s, 3H), 2.95-2.81 (m, 2H), 1.89-1.73 (m, 4H),1.62-1.53 (m, 1H), 1.31-1.19 (m, 1H). 3-isopropyl-N-[2-[2-[(1- I-340 1HNMR (400 MHz, CD3OD) δ: 8.28 474.3 methylpyrazol-4- (d, J = 5.2 Hz, 1H),7.86 (s, 1H), 7.83 yl)amino]pyrimidin-4-yl]- (d, J = 8.0 Hz, 1H), 7.77(s, 1H), 7.55 6,7,8,9-tetrahydro-5H- (s, 1H), 7.29-7.26 (m, 1H), 7.09(d, J = benzo[7]annulen-5- 5.2 Hz, 1H), 6.46-6.40 (m, 1H), 5.06-yl]pyrrolidine-1-carboxamide 4.99 (m, 1H), 3.78 (s, 3H), 3.63-3.46 (m,2H), 3.28-3.24 (m, 1H), 2.98-2.82 (m, 3H), 2.05-1.99 (m, 1H), 1.91-1.76(m, 5H), 1.65-1.43 (m, 3H), 1.32-1.24 (m, 1H), 0.91-0.89 (m, 6H)N-[2-[2-[(1-ethylpyrazol-4- I-341 1H NMR (400 MHz, CD3OD) δ: 8.28 488.1yl)amino]pyrimidin-4-yl]- (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.836,7,8,9-tetrahydro-5H- (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.56benzo[7]annulen-5-yl]-3- (s, 1H), 7.29-7.26 (m, 1H), 7.09 (d, J =isopropyl-pyrrolidine-1- 5.2 Hz, 1H), 5.02 (t, J = 8.8 Hz, 1H),carboxamide 4.08 (q, J = 7.2 Hz, 2H), 3.63-3.46 (m, 2H), 3.26-3.24 (m,1H), 2.98-2.82 (m, 3H), 2.04-1.99 (m, 1H), 1.91-1.78 (m, 5H), 1.63-1.43(m, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.29-1.27 (m, 1H), 0.92-0.89 (m, 6H).3-isopropyl-N-[2-[2-[(1- I-342 1H NMR (400 MHz, CD3OD) δ: 8.29 544.3tetrahydropyran-4-ylpyrazol- (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 7.92-4-yl)amino]pyrimidin-4-yl]- 7.71 (m, 2H), 7.59 (s, 1H), 7.34-7.226,7,8,9-tetrahydro-5H- (m, 1H), 7.10 (d, J = 5.2 Hz, 1H), 6.55-benzo[7]annulen-5- 6.33 (m, 1H), 5.12-4.98 (m, 1H), 4.35-yl]pyrrolidine-1-carboxamide 4.19 (m, 1H), 3.99-3.97 (m, 2H), 3.69- 3.41(m, 4H), 3.34-3.24 (m, 1H), 3.10- 2.77 (m, 3H), 2.11-1.73 (m, 10H),1.72- 1.36 (m, 3H), 1.35-1.22 (m, 1H), 0.98- 0.80 (m, 6H)3-tert-butoxy-N-[2-[2-[[1-(4- I-343 1H NMR (400 MHz, CD3OD) δ: 8.40559.4 piperidyl)pyrazol-4- (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.92yl]amino]pyrimidin-4-yl]- (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.736,7,8,9-tetrahydro-5H- (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21benzo[7]annulen-5- (d, J = 6.4 Hz, 1H), 5.05 (d, J = 10.4yl]azetidine-1-carboxamide Hz, 1H), 4.64-4.59 (m, 1H), 4.53-4.45 (m,1H), 4.27-4.19 (m, 2H), 3.88-3.70 (m, 2H), 3.53-3.50 (m, 2H), 3.21-3.13(m, 2H), 3.07-2.92 (m, 2H), 2.34-2.14 (m, 4H), 2.01-1.86 (m, 4H),1.72-1.64 (m, 1H), 1.43-1.37 (m, 1H), 1.23 (s, 9H).3-isopropyl-N-[2-[2-[[1- I-344 1H NMR (400 MHz, CD3OD) δ: 8.28 530[(3R)-tetrahydrofuran-3- (d, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.83yl]pyrazol-4- (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.54yl]amino]pyrimidin-4-yl]- (s, 1H), 7.29-7.26 (m, 1H), 7.10 (d, J =6,7,8,9-tetrahydro-5H- 5.2 Hz, 1H), 6.46-6.40 (m, 1H), 5.04-benzo[7]annulen-5- 5.02 (m, 1H), 4.94-4.90 (m, 1H), 4.04-yl]pyrrolidine-1-carboxamide 3.93 (m, 3H), 3.82-3.80 (m, 1H), 3.61- 3.49(m, 2H), 3.28-3.26 (m, 1H), 2.95- 2.90 (m, 3H), 2.41-2.39 (m, 3H), 2.04-2.01 (m, 1H), 1.93-1.92 (m, 1H), 1.91- 1.82 (m, 5H), 1.63-1.50 (m, 3H),1.30- 1.28 (m, 1H), 0.92-0.89 (m, 6H). 3-isopropyl-N-[2-[2-[[1- I-345 1HNMR (400 MHz, CD3OD) δ: 8.28 530.3 [(3S)-tetrahydrofuran-3- (d, J = 5.2Hz, 1H), 8.08 (s, 1H), 7.86- yl]pyrazol-4- 7.74 (m, 2H), 7.56 (s, 1H),7.30 (dd, J = yl]amino]pyrimidin-4-yl]- 8.0, 1.6 Hz, 1H), 7.10 (d, J =5.2 Hz, 6,7,8,9-tetrahydro-5H- 1H), 6.51-6.37 (m, 1H), 5.06-5.04 (m,benzo[7]annulen-5- 1H), 4.93-4.91 (m, 1H), 4.10-3.87 (m,yl]pyrrolidine-1-carboxamide 3H), 3.86-3.77 (m, 1H), 3.65-3.43 (m, 2H),3.35-3.25 (m, 1H), 3.01-2.85 (m, 3H), 2.47-2.35 (m, 1H), 2.26-2.16 (m,1H), 2.10-1.97 (m, 1H), 1.96-1.74 (m, 4H), 1.69-1.18 (m, 5H), 0.91 (d, J= 5.6 Hz, 6H). N-[2-(2-hydroxyethyl)-8-[2- I-346 ¹H NMR (500 MHz, CD₃OD)δ: 8.29 521 [(1-methylpyrazol-4- (d, J = 3.6 Hz, 1H), 7.91-7.87 (m, 3H),yl)amino]pyrimidin-4-yl]- 7.53 (s, 1H), 7.31 (d, J = 6.4 Hz, 1H),1,3,4,5-tetrahydro-2- 7.11 (d, J = 4.0 Hz, 1H), 5.08 (d, J =benzazepin-5-yl]-3- 8.0 Hz, 1H), 4.36-4.33 (m, 1H), 4.16-isopropoxy-azetidine-1- 4.09 (m, 2H), 4.03-3.99 (m, 1H), 3.94-carboxamide 3.91 (m, 1H), 3.79 (s, 3H), 3.79-3.73 (m, 2H), 3.61-3.57 (m,3H), 3.15-3.12 (m, 1H), 3.06-3.04 (m, 1H), 2.54-2.46 (m, 2H), 1.99-1.96(m, 1H), 1.76-1.73 (m, 1H), 1.08 (d, J = 4.8 Hz, 1H).3-tert-butoxy-N-[2-[2-[(1,5- I-347 1H NMR (400 MHz, CDCl3) δ: 8.36 (d,504.3 dimethylpyrazol-4- J = 5.2 Hz, 1H), 7.79-7.78 (m, 2H), 7.70yl)amino]pyrimidin-4-yl]- (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.046,7,8,9-tetrahydro-5H- (d, J = 5.2 Hz, 1H), 6.41 (s, 1H), 5.08 (t,benzo[7]annulen-5- J = 8.0 Hz, 1H), 4.54-4.41 (m, 2H),yl]azetidine-1-carboxamide 4.20-4.10 (m, 2H), 3.94-3.84 (m, 2H), 3.81(s, 3H), 3.02-2.83 (m, 2H), 2.23 (s, 3H), 1.98-1.69 (m, 6H), 1.20 (s,9H). N-[2-[2-[[1-(3-fluoro-1- I-348 ¹H NMR (400 MHz, CD₃OD) δ: 8.39577.5 methyl-4-piperidyl)pyrazol-4- (d, J = 6.4 Hz, 1H), 8.13 (s, 1H),7.94- yl]amino]pyrimidin-4-yl]- 7.90 (m, 2H), 7.72 (s, 1H), 7.38 (d, J =6,7,8,9-tetrahydro-5H- 10.8 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H),benzo[7]annulen-5-yl]-3- 5.06-5.03 (m, 1H), 4.99-4.95 (m, 1H),isopropoxy-azetidine-1- 4.46-4.43 (m, 1H), 4.28-4.18 (m, 3H),carboxamide 3.89-3.87 (m, 2H), 3.70-3.66 (m, 1H), 3.08-2.95 (m, 3H),2.39 (s, 3H), 2.29- 1.65 (m, 9H), 1.39-1.35 (m, 2H), 1.19 (d, J = 7.6Hz, 6H). 4-isobutyl-1-[[2-methyl-4-[2- I-349 ¹H NMR (400 MHz, CD₃OD) δ:8.31 (s, 488.3 [[1-(1-methylazetidin-3- 1H), 8.00 (s, 1H), 7.95-7.87 (m,2H), yl)pyrazol-4- 7.80 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H),yl]amino]pyrimidin-4- 7.25 (d, J = 5.6 Hz, 1H), 5.30 (d, J = 6.8yl]phenyl]methyl]piperazin-2- Hz, 1H), 4.81-4.73 (m, 1H), 4.69 (s,oneacid 2H), 4.66-4.54 (m, 1H), 4.51-4.28 (m, 2H), 4.00 (s, 2H),3.63-3.43 (m, 4H), 3.10-2.99 (m, 4H), 2.94 (s, 1H), 2.33 (s, 3H),2.17-2.03 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H).4-(2,2-dimethylpropyl)-1-[[4- I-350 ¹H NMR (400 MHz, CD₃OD) δ: 8.58 (s,532.3 [2-[[1-(2- 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.40 (d, Jhydroxyethyl)pyrazol-4- = 8.4 Hz, 1H), 8.05 (s, 1H), 7.70-7.63yl]amino]pyrimidin-4-yl]-2- (m, 2H), 7.34 (d, J = 5.6 Hz, 1H), 4.96(trifluoromethyl)phenyl]meth (s, 2H), 4.23 (t, J = 5.2 Hz, 2H), 4.10 (s,yl]piperazin-2-oneacid 2H), 3.91 (t, J = 5.6 Hz, 2H) 3.64 (brs, 4H),3.13 (s, 2H), 1.14 (s, 9H). 3-isopropoxy-N-[[4-[2-[[1-(2- I-351 ¹H NMR(400 MHz, CD₃OD) δ: 8.44- 534.2 methoxyethyl)pyrazol-4- 8.31 (m, 2H),8.22 (d, J = 8.0 Hz, 1H), yl]amino]pyrimidin-4-yl]-2- 7.95 (s, 1H),7.62-7.50 (m, 2H), 7.16 (d, (trifluoromethyl)phenyl]meth J = 5.2 Hz,1H), 4.50 (s, 2H), 4.38-4.29 yl]azetidine-1-carboxamide (m, 1H), 4.18(t, J = 5.2 Hz, 2H), 4.13- 4.03 (m, 2H), 3.76-3.70 (m, 2H), 3.65 (t, J =5.2 Hz, 2H), 3.61-3.51 (m, 1H), 3.24 (s, 3H), 1.07 (d, J = 6.0 Hz, 6H).3-isopropoxy-N-[7-[2-[(1- I-352 1H NMR (400 MHz, CD3OD) δ: 8.29 477methylpyrazol-4- (d, J = 5.2 Hz, 1H), 7.86-7.85 (m, 2H),yl)amino]pyrimidin-4-yl]- 7.80 (s, 1H), 7.55 (s, 1H), 7.30 (d, J =2,3,4,5-tetrahydro-1H-3- 8.0 Hz, 1H), 7.10 (d, J = 5.2 Hz, 1H),benzazepin-1-yl]azetidine-1- 4.98 (d, J = 6.4 Hz, 1H), 4.35-4.31 (mcarboxamide 1H), 4.14-4.08 (m, 2H), 3.79 (s, 3H), 3.76-3.72 (m, 2H),3.60-3.54 (m, 1H), 3.02-2.79 (m, 6H), 1.06 (d, J = 6.4 Hz, 6H).N-[[2-chloro-4-[2-[[1-(1- I-353 ¹H NMR (400 MHz, CD₃OD) δ: 8.34 511.2methylazetidin-3-yl)pyrazol- (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 8.014-yl]amino]pyrimidin-4- (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74yl]phenyl]methyl]-3- (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.13isopropoxy-azetidine-1- (d, J = 5.2 Hz, 1H), 5.24-5.19 (m, 1H),carboxamide 4.53-4.48 (m, 2H), 4.38-4.30 (m, 5H), 4.11-4.07 (m, 2H),3.74-3.70 (m, 2H), 3.59-3.53 (m, 1H), 2.94 (s, 3H), 1.06 (d, J = 6.0 Hz,6H). 5-tert-butyl-N-[[2-chloro-4- I-354 ¹H NMR (400 MHz, CD₃OD) δ: 8.34521.3 [2-[[1-(1-methylazetidin-3- (d, J = 4.8 Hz, 1H), 8.13 (d, J = 2.0Hz, yl)pyrazol-4- 1H), 8.09 (s, 1H), 7.95 (dd, J = 8.0, 2.0yl]amino]pyrimidin-4- Hz, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.4yl]phenyl]methyl]isoxazole- Hz, 1H), 7.13 (d, J = 5.2 Hz, 1H), 6.393-carboxamide (s, 1H), 4.90-4.78 (m, 1H), 4.62 (s, 2H), 3.78-3.74 (m,2H), 3.52-3.47 (m, 2H), 2.36 (s, 3H), 1.29 (s, 9H).5-tert-butyl-N-[[4-[2-[[1-(1- I-355 ¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s,555.3 methylazetidin-3-yl)pyrazol- 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.24(d, J = 4-yl]amino]pyrimidin-4-yl]-2- 7.6 Hz, 1H), 8.06 (s, 1H), 7.64(s, (trifluoromethyl)phenyl]meth 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.19 (d,J = yl]isoxazole-3-carboxamide 5.2 Hz, 1H), 6.41 (s, 1H), 5.00-4.93 (m,1H), 4.74 (s, 2H), 3.99-3.94 (m, 2H), 3.74-3.72 (m, 2H), 2.52 (s, 3H),1.30 (s, 9H). 1-tert-butyl-N-[[2-chloro-4- I-356 ¹H NMR (400 MHz, CD₃OD)δ: 8.46 520.3 [2-[[1-(1-methylazetidin-3- (d, J = 5.2 Hz, 1H), 8.29 (s,1H), 8.24 yl)pyrazol-4- (s, 1H), 8.20 (br, 1H), 8.06 (d, J = 8.0yl]amino]pyrimidin-4- Hz, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.54yl]phenyl]methyl]pyrazole-4- (d, J = 8.0 Hz, 1H), 7.25 (d, J = 4.0 Hz,carboxamide 1H), 5.01-4.90 (m, 1H), 4.69 (s, 2H), 3.88 (t, J = 8.0 Hz,2H), 3.61 (t, J = 8.0 Hz, 2H), 2.48 (s, 3H), 1.63 (s, 9H).2-tert-butyl-N-[[2-methyl-4- I-357 ¹H NMR (400 MHz, CDCl₃) δ: 8.77 (s,518.2 [6-[[1-[(3R)-tetrahydrofuran- 1H), 8.04 (s, 1H), 7.91 (s, 1H),7.82 (d, 3-yl]pyrazol-3- J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J =yl]amino]pyrimidin-4- 2.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H),yl]phenyl]methyl]thiazole-5- 7.24 (s, 1H), 6.26 (s, 1H), 6.08 (t, J =carboxamide 5.2 Hz, 1H), 4.92-4.88 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H),4.20-4.07 (m, 3H), 4.01-3.95 (m, 1H), 2.49-2.36 (m, 5H), 1.45 (s, 9H).2-tert-butyl-N-[[2-methyl-4- I-358 ¹H NMR (400 MHz, CD₃OD) δ: 8.48 (s,545.2 [6-[[1-(1-methyl-4- 1H), 8.13 (s, 1H), 7.69 (s, 1H), 7.65 (d,piperidyl)pyrazol-3- J = 8.0 Hz, 1H), 7.53-7.50 (m, 1H),yl]amino]pyrimidin-4- 7.49 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0yl]phenyl]methyl]thiazole-5- Hz, 1H), 6.26 (s, 1H), 4.50 (s, 2H),carboxamide 4.05-3.97 (m, 1H), 2.89 (d, J = 11.6 Hz, 2H), 2.35 (s, 3H),2.22 (s, 3H), 2.17- 2.09 (m, 2H), 2.04-1.99 (m, 4H), 1.35 (s, 9H).3-tert-butoxy-N-[6-[2-[(1- I-359 ¹H NMR (400 MHz, CD₃OD) δ: 8.36 476.2methylpyrazol-4- (d, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.89yl)amino]pyrimidin-4- (d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.63yl]tetralin-1-yl]azetidine-1- (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.15carboxamide (d, J = 5.2 Hz, 1H), 4.97-4.96 (m, 1H), 4.60-4.52 (m, 1H),4.19-4.10 (m, 2H), 3.88 (s, 3H), 3.81-3.71 (m, 2H), 2.87- 2.85 (m, 2H),2.11-1.95 (m, 2H), 1.90- 1.72 (m, 2H), 1.19 (s, 9H).N-[[4-[2-[(1-ethylpyrazol-4- I-360 1H NMR (400 MHz, METHANOL-d4) 450.3yl)amino]pyrimidin-4-yl]-2- δ: 8.15-8.40 (m, 1 H) 7.92-8.11 (m, 3methyl-phenyl]methyl]-3- H) 7.63-7.80 (m, 1 H) 7.53 (d, J = 6.53isopropoxy-azetidine-1- Hz, 1 H) 7.45 (d, J = 8.53 Hz, 1 H) 4.35-carboxamideacid 4.48 (m, 3 H) 4.12-4.29 (m, 4 H) 3.81 (dd, J = 9.04,4.52 Hz, 2 H) 3.57-3.72 (m, 1 H) 2.43 (s, 3 H) 2.03 (s, 2 H) 1.51 (t, J= 7.28 Hz, 3 H) 1.16 (d, J = 6.02 Hz, 6H)

Example 239: Protocol for Human B Cell Stimulation

Human B cells are purified from 150 ml of blood. Briefly, the blood isdiluted 1/2 with PBS and centrifuged through a Ficoll density gradient.The B cells are isolated from the mononuclear cells by negativeselection using the B cell isolation kit II from Milenyi (Auburn,Calif.). 50,000 B cells per well are then stimulated with 10 ug/ml ofgoat F(ab′)₂ anti-human IgM antibodies (Jackson ImmunoResearchLaboratories, West Grove, Pa.) in a 96-well plate. Compounds are dilutedin DMSO and added to the cells. Final concentration of DMSO is 0.5%.Proliferation is measured after 3 days using Promega CellTiter-Glo(Madison, Wis.).

Example 240: In Vitro BTK Kinase Assay: BTK-POLYGAT-LS ASSAY

The purpose of the BTK in vitro assay is to determine compound potencyagainst BTK through the measurement of IC₅₀. Compound inhibition ismeasured after monitoring the amount of phosphorylation of afluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presenceof active BTK enzyme (Upstate 14-552), ATP, and inhibitor. The BTKkinase reaction was done in a black 96 well plate (costar 3694). For atypical assay, a 24 μL aliquot of a ATP/peptide master mix (finalconcentration; ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mMTris-HCl pH 7.5, 10 mM MgCl₂, 200 μM Na₃PO₄, 5 mM DTT, 0.01% TritonX-100, and 0.2 mg/ml casein) is added to each well. Next, 1 μL of a4-fold, 40× compound titration in 100% DMSO solvent is added, followedby adding 15 uL of BTK enzyme mix in 1× kinase buffer (with a finalconcentration of 0.25 nM). The assay is incubated for 30 minutes beforebeing stopped with 28 μL of a 50 mM EDTA solution. Aliquots (5 μL) ofthe kinase reaction are transferred to a low volume white 384 well plate(Corning 3674), and 5 μL of a 2× detection buffer (Invitrogen PV3574,with 4 nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate iscovered and incubated for 45 minutes at room temperature. Time resolvedfluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nmemission; 518 nm fluorescein emission) is measured. IC₅₀ values arecalculated using a four parameter fit with 100% enzyme activitydetermined from the DMSO control and 0% activity from the EDTA control.

Table 1 shows the activity of selected compounds of this invention inthe in vitro Btk kinase assay, wherein each compound number correspondsto the compound numbering set forth in Examples 1-238 herein, supra.Compounds have an activity designated as “A” provided an IC₅₀<10 nM;compounds having an activity designated as “B” provided an IC₅₀ of 10-99nM; compounds having an activity designated as “C” provided an IC₅₀ of100-999 nM; compounds having an activity designated as “D” provided anIC₅₀ of 1,000-10,000 nM; and compounds having an activity designated as“E” provided an IC₅₀ of >10,000 nM. In some instances where a compoundtested has activity “E”, other structurally similar compounds beyond themeasurable limits of the assay are not included in Table 1.

TABLE 1 Inhibitory Data for Exemplary Compounds Compound tested IC50(10uMATP) I-1 A I-2 A I-3 A I-4 A I-5 A I-6 A I-7 A I-8 A I-9 A I-10 A I-11B I-12 A I-13 A I-14 B I-15 A I-16 E I-17 C I-18 C I-19 A I-20 A I-21 AI-22 B I-23 C I-24 B I-25 D I-26 D I-27 E I-28 E I-29 D I-30 D I-31 CI-32 C I-33 C I-34 B I-35 D I-36 A I-37 A I-38 A I-39 A I-40 A I-41 AI-42 A I-43 A I-44 A I-45 A I-46 A I-47 A I-48 A I-49 A I-50 A I-51 AI-52 A I-53 C I-54 A I-55 A I-56 A I-57 A I-58 B I-59 B I-60 B I-61 BI-62 A I-63 A I-64 A I-65 A I-66 A I-67 A I-68 B I-69 A I-70 A I-71 BI-72 D I-73 D I-74 D I-75 D I-76 E I-77 D I-78 E I-79 D I-80 D I-81 DI-82 C I-83 C I-84 D I-85 B I-86 B I-87 C I-88 C I-89 A I-90 B I-91 AI-92 B I-93 B I-94 C I-95 A I-96 B I-97 A I-98 B I-99 A I-100 B I-101 BI-102 B I-103 B I-104 C I-105 B I-106 A I-107 D I-108 A I-109 B I-110 BI-111 A I-112 A I-113 C I-114 C I-115 A I-116 A I-117 B I-118 A I-119 CI-120 A I-121 A I-122 A I-123 A I-124 A I-125 A I-126 A I-127 A I-128 AI-129 A I-130 A I-131 A I-132 A I-133 A I-134 A I-135 A I-136 B I-137 AI-138 D I-139 B I-140 B I-141 C I-142 A I-143 A I-144 B I-145 C I-146 CI-147 A I-148 A I-149 A I-150 A I-151 A I-152 A I-153 A I-154 A I-155 BI-156 C I-157 B I-158 C I-159 A I-160 A I-161 A I-163 A I-164 A I-166 AI-167 A I-168 A I-169 A I-171 A I-172 A I-173 A I-174 A I-175 A I-176 AI-178 A I-179 A I-180 A I-181 A I-182 A I-183 A I-184 A I-185 A I-186 AI-187 A I-188 A I-189 A I-190 A I-191 A I-192 A I-193 A I-194 A I-195 AI-196 A I-197 A I-198 A I-199 A I-200 A I-201 A I-202 A I-203 A I-204 AI-205 A I-206 A I-207 A I-208 A I-209 A I-210 A I-211 A I-212 A I-213 AI-214 A I-215 A I-216 A I-217 A I-218 A I-219 A I-220 A I-221 A I-222 AI-223 A I-224 A I-225 A I-226 A I-227 A I-229 A I-231 A I-232 A I-233 AI-234 A I-235 A I-236 A I-237 A I-238 A I-239 A I-240 A I-241 A I-242 AI-243 A I-244 A I-245 A I-246 A I-247 A I-248 A I-249 A I-250 A I-251 AI-252 A I-253 A I-254 A I-255 A I-256 A I-257 I-258 A I-259 A I-260 AI-261 A I-262 I-263 A I-264 A I-265 A I-266 A I-267 A I-268 A I-269 AI-270 A I-271 A I-272 A I-273 A I-274 A I-275 A I-276 A I-277 A I-278 AI-279 A I-280 A I-281 A I-282 A I-283 A I-284 A I-285 A I-286 A I-287 AI-288 A I-289 A I-290 A I-291 A I-292 A I-293 A I-294 A I-295 A I-296 AI-297 A I-298 A I-299 A I-300 B I-301 A I-302 A I-303 A I-304 A I-305 AI-306 A I-307 A I-308 A I-309 A I-310 A I-311 A I-312 A I-313 A I-314 AI-315 A I-316 A I-317 A I-318 A I-319 A I-320 A I-321 A I-322 A I-323 AI-324 A I-325 A I-326 A I-327 A I-328 A I-329 A I-330 A I-331 A I-332 AI-333 A I-334 A I-335 A I-336 A I-337 A I-338 A I-339 B I-340 A I-341 AI-342 A I-343 A I-344 A I-345 A I-346 A I-347 A I-348 A I-349 A I-350 AI-351 A I-352 B I-353 A I-354 A I-355 A I-356 A I-357 A I-358 A I-359 AI-360 A

Example 241: —In Vitro Inhibition of BTK Activity in Mouse Whole Blood

Anti-rabbit MSD plates (Meso Scale Discovery, Rockville, Md.) are coatedwith 35 uL/well of rabbit anti-BTK C82B8 (Cell Signaling Technology,Danvers, Mass.) diluted 1:50 in PBS. Plates are incubated for 2 hours±1hour at room temp, shaking (setting 3-5) or ON at 4° C. Plates areblocked with MSD Blocker A (Meso Scale Discovery, Rockville, Md.) using3% MSD Blocker A in TBST. Coated plates are first washed 3× with 250uL/well TBST followed by addition of 200 uL/well 3% Blocker A/TBST.Plates are blocked for >2 hour at RT, shaking or ON at 4° C.

Whole blood is collected from DBA/1 mice in 16×100 sodium heparin tubes(Becton Dickinson, Cat No. 367874). Blood from multiple DBA/1 mice ispooled. 96 uL of whole blood per well is aliquotted into a 96-roundbottom plate changing tips each time. 4 uL diluted test compound isadded to each sample, mixed, and incubated for 30 min at 37° C.

For serial dilutions of test compound, 1000× plate is produced withserial dilutions of test compound in 100% DMSO. Ten dilutions, done 1:3,starting at 10 mM are created by: adding 15 uL of test compound at 10 mMin 100% DMSO to well A1; adding 10 uL 100% DMSO to wells A2-A12;diluting 5 uL from well A1 to well A2 and mixing; continuing 1:3 serialdilutions, changing tips between transfers, to well A10. Wells A11 andA12 contain 100% DMSO without test compound.

For dilution 1, a 1:40 plate is created. Using a 12-well multi-channelpipette, each concentration of test compound or DMSO is diluted 1:40 byadding 2 uL from each well of 1000× stock plate to 78 uL water andmixing.

For dilution 2, test compound or DMSO are added to whole blood bydiluting 1:25. Using a 12-well multi-channel pipette, 4 uL from 1:40plate (B) is added to 96 uL whole blood and mixed.

The final concentration of test compounds are shown below. Theconcentration of DMSO is 0.1% final in each well.

(+PPi) (−PPi) 1 2 3 4 5 6 7 8 9 10 11 12 A 10000 nM 3333 nM 1111 nM 370nM 123 nM 41 nM 14 nM 5 nM 2 nM 0.5 nM 0 nM 0 nM B 10000 nM 3333 nM 1111nM 370 nM 123 nM 41 nM 14 nM 5 nM 2 nM 0.5 nM 0 nM 0 nM C 10000 nM 3333nM 1111 nM 370 nM 123 nM 41 nM 14 nM 5 nM 2 nM 0.5 nM 0 nM 0 nM

Lysing buffer used to lyse whole blood is prepared as follows. A 10×Lysis buffer is prepared using 1500 mM NaCl; 200 mM Tris, pH 7.5; 10 mMEDTA; 10 mM EGTA; and 10% Triton-X-100. The 10× Lysis buffer is dilutedto 1× in dH₂O, and complete lysing buffer (+/−phosphatase inhibitors) isprepared as follows:

+PPi (mL) −PPi (mL) 1X Lysis buffer 10 10 500 mM PMSF in DMSO 0.02 0.02Phosphatase Inhibitor 3 0.1 Phosphatase Inhibitor 2 0.1 ProteaseInhibitor (cOmplete) (1 tablet for 10 mL) 1 tablet 1 tablet PhosStop (1tablet for 10 mL) 1 tablet Sodium Orthovanadate (Na₃VO₄) (50 uM final)0.1 Sodium Fluoride (NaF) (10 mM final) 0.005 1% Deoxycholate (0.25%final) 2.5 2.5

100 uL of complete lysing buffer (+/−phosphatase inhibitors) is added toeach well, and mixed well by pipetting up and down a few times. Wells1-10 and 12 received 1× Lysis buffer containing phosphatase inhibitors(+PPi) and well 11 receive 1× Lysis buffer without phosphataseinhibitors (−PPi). Samples are incubated for 1 hour on ice or at 4° C.Samples are mixed again at half time point for complete lysing.

Blocking buffer is washed off blocked MSD plates with 250 uL TBST perwell 3 times. 100-150 uL of whole blood lysates is added to each well ofthe coated and blocked MSD plates followed by incubation overnight in acold room with shaking.

The plates are then washed 4 times with 250 μL TBST per well.Biotinylated phospho-tyrosine mouse mAb (pY100, Cell SignalingTechnology, Danvers, Mass.) was diluted 1:125 in 1% Blocker A. Mouseanti-BTK mAb (Fitzgerald Industries International, Acton, Mass.) isdiluted 1:900 in 1% Blocker A. 35 μL of diluted pY100 or dilutedanti-BTK mAb is added to each well and incubated for 2 hours at roomtemperature, shaking.

Plates are then washed 3 times with 250 uL TBST/well. 35 uL of 1:500Streptavidin-Sulfo-Tag labeled antibody in 3% Blocker A is added to eachwell. For anti-BTK, 35 uL of 1:500 anti-mouse-Tag labeled antibody in 3%Blocker A is added to each well. Plates are incubated for 1 hour at RT,shaking.

To develop and read the plates, 1× Read Buffer in dH₂O is prepared from4× stock. Plates are washed 3 times with 250 uL TBST/well. 150 uL of1×MSD Read Buffer is added to each well. Plates are read in a SECTORImager 6000 (Meso Scale Discovery, Rockville, Md.).

Materials ITEM VENDOR CATALOG NO. Anti-rabbit MSD plates MSD L45RA-1Rabbit anti-BTK (C82B8) Cell Signaling 3533S PBS Media Prep MSD BlockerA MSD R93BA-4 TBST (1xTBS/0.1% Tween20) Media Prep 10X Lysing BufferMedia Prep PMSF in DMSO (500 mM) Media Prep Phosphatase CocktailInhibitor 3 Sigma Aldrich P0044-5ML Phosphatase Cocktail Inhibitor 2Sigma Aldrich P5726-1ML cOmplete Mini Roche 11 836 153 001 PhosStopInhibitor Roche 04 906 837 001 Sodium Orthovanadate 100 mM Media PrepSodium Fluoride 1M Media Prep 1% Deoxycholate Media Prep pTyr 100 ms mAbbiotinylated Cell Signaling 9417S Streptavidin Sulfo-Tag MSD R32AD-1 MSDRead Buffer 4X MSD R92TC-1 Costar 96-round bottom Costar/Fisher 3799Mouse anti-BTK (7F12H4) Fitzgerald 10R-1929 Anti-mouse Sulfo-Tag MSDR32AC-5

Example 242—PK/PD Correlation in DBA1 Mice

Mice are dosed orally (PO) with test compound in CMC-Tween and killed byCO₂ asphyxiation at various times after dosing. Heparinized whole bloodis immediately collected by cardiac puncture and split into two samples.One sample is used to quantify the amount of test compound present andthe other is lysed in MSD lysis buffer in the presence of phosphataseinhibitors. Heparinized whole blood from cardiac punctures of vehicle(CMC-Tween) dosed mice are lysed either in the presence (high control)or absence (low control) of phosphatase inhibitors. Lysed whole bloodsamples are analyzed for phospho-BTK as described above. The percentinhibition of phospho-BTK in each whole blood sample from dosed mice iscalculated as follows:(1−((pBTK(x+PPi)−pBTK(vehicle−PPi))/(pBTK(vehicle+PPi))))*100, wherepBTK(x+PPi) is the ECL signal for whole blood from each testcompound-treated mouse, pBTK(vehicle−PPi) is the average ECL signal ofwhole blood from vehicle-treated mice lysed in the absence ofphosphatase inhibitors (low control) and pBTK(vehicle+PPi) is theaverage ECL signal of whole blood from vehicle-treated mice lysed in thepresence of phosphatase inhibitors (high control).

Example 243: In Vitro PD Assay in Human Whole Blood

Human heparinized venous blood was purchased from Bioreclamation, Inc.or SeraCare Life Sciences and shipped overnight. Whole blood wasaliquoted into 96-well plate and “spiked” with serial dilutions of testcompound in DMSO or with DMSO without drug. The final concentration ofDMSO in all wells was 0.1%. The plate was incubated at 37° C. for 30min. Lysis buffer containing protease and phosphatase inhibitors wasadded to the drug-containing samples and one of the DMSO-only samples(+PPi, high control), while lysis buffer containing protease inhibitorswas added to the other DMSO-only samples (−PPi, low control). All of thelysed whole blood samples were subjected to the total BTK capture andphosphotyrosine detection method described in Example 241. ECL valueswere graphed in Prism and a best-fit curve with restrictions on themaximum and minimum defined by the +PPi high and −PPi low controls wasused to estimate the test compound concentration that results in 50%inhibition of ECL signal by interpolation.

Table 2 shows the activity of selected compounds of this invention inthe pBTK assay, wherein each compound number corresponds to the compoundnumbering set forth in Examples 1-238 herein, supra. Compounds have anactivity designated as “A” provided an IC₅₀<500 nM; compounds having anactivity designated as “B” provided an IC₅₀ of 500-1499 nM; compoundshaving an activity designated as “C” provided an IC₅₀ of 1500-10000 nM.In some instances where a compound tested has activity “C”, otherstructurally similar compounds beyond the measurable limits of the assayare not included in Table 2.

TABLE 2 pBTK Inhibitory Data for Exemplary Compounds Compound TestedpBTK IC50 I-1 A I-2 B I-3 C I-4 C I-5 B I-6 B I-7 B I-9 B I-10 A I-12 AI-13 C I-15 A I-19 B I-20 B I-21 A I-23 C I-24 C I-36 A I-37 A I-38 BI-39 A I-40 A I-41 A I-42 A I-43 A I-44 A I-45 A I-46 A I-47 B I-48 AI-49 A I-50 A I-51 B I-52 A I-54 B I-55 C I-56 B I-62 C I-63 A I-64 CI-65 B I-66 B I-67 B I-69 A I-70 A I-89 B I-91 C I-95 B I-99 C I-108 CI-111 C I-115 B I-116 B I-118 A I-120 B I-121 A I-122 A I-123 A I-124 AI-125 A I-126 A I-127 B I-128 A I-129 B I-130 A I-131 B I-132 C I-135 CI-142 C I-160 A I-161 A I-163 A I-164 A I-166 A I-167 A I-168 A I-169 AI-171 A I-172 A I-173 A I-174 A I-175 A I-176 A I-178 A I-179 A I-180 AI-181 A I-182 A I-183 A I-184 A I-185 A I-186 A I-187 A I-188 B I-189 AI-190 A I-191 A I-192 A I-193 A I-194 A I-195 A I-196 A I-197 A I-198 AI-199 A I-200 A I-201 A I-202 A I-203 A I-204 A I-205 A I-206 A I-207 AI-208 A I-209 A I-210 A I-211 A I-212 A I-213 A I-214 A I-215 A I-216 AI-217 A I-218 A I-219 A I-220 A I-221 A I-222 B I-223 B I-224 A I-225 AI-226 A I-227 A I-229 A I-231 A I-232 A I-233 A I-234 A I-235 A I-236 AI-237 A I-238 A I-239 A I-240 A I-241 A I-242 A I-243 A I-244 A I-245 AI-246 A I-247 A I-248 A I-249 A I-250 A I-251 A I-252 A I-253 A I-254 AI-255 A I-256 A I-257 A I-258 A I-259 A I-260 A I-261 A I-262 A I-263 AI-264 A I-265 A I-266 A I-267 A I-268 A I-269 A I-270 A I-271 A I-272 AI-273 A I-274 A I-275 A I-276 A I-277 A I-278 A I-279 A I-280 A I-281 AI-282 A I-283 A I-284 A I-285 A I-286 A I-287 A I-288 A I-289 A I-290 AI-291 A I-292 A I-293 A I-294 A I-295 A I-296 A I-297 A I-298 A I-299 AI-300 A I-301 A I-302 A I-303 A I-304 A I-305 A I-306 A I-307 A I-308 AI-309 A I-310 A I-311 A I-312 A I-313 A I-314 A I-315 A I-316 A I-317 AI-318 A I-319 A I-320 A I-321 A I-322 A I-323 A I-324 A I-325 A I-326 AI-327 A I-328 A I-329 A I-330 A I-331 A I-332 A I-333 A I-334 A I-335 AI-336 A I-337 A I-338 A I-339 A I-340 A I-341 A I-342 A I-343 A I-344 AI-345 A I-346 A I-347 A I-348 A I-349 A I-350 A I-351 A I-352 A I-353 AI-354 A I-355 A I-356 A I-357 A I-358 A I-359 A I-360 A

EQUIVALENTS

It is to be understood that while the disclosure has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1-36. (canceled)
 37. A method of decreasing the enzymatic activity ofBruton's tyrosine kinase comprising contacting Bruton's tyrosine kinasewith an effective amount of a compound of Formula I′:

or a pharmaceutically acceptable salt, wherein: one of A¹ and A² isC—R⁶, and the other of A¹ and A² is selected from C—R⁶ or N; A³ isselected from C—H or N, and is C—H when A¹ or A² is N; Q¹ is selectedfrom C—R⁷ and N; Q² is selected from C—R⁷ and N; Q³ is selected fromC—R⁷ and N; wherein at most one of Q¹, Q², and Q³ is N; R¹ is selectedfrom —N(R)₂, phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl areoptionally substituted with one or more R¹⁰; R² is H or C₁₋₆ aliphatic;or R¹ and R², together with their intervening atoms, form a ringselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, 7- to 10-membered bicyclic heterocyclyl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, or 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, wherein said ring is optionally substituted with oneor more R²⁰; R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR,—C(O)R, and C₁₋₆ aliphatic, wherein the C₁₋₆ aliphatic group isoptionally substituted with hydroxyl; each R⁴ is independently selectedfrom halogen, —NO₂, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R,—S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,—N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic, wherein said C₁₋₆ aliphaticis optionally substituted with one or more R⁴⁰; or R³ and R⁴ togetherwith their intervening atoms form fused Ring A selected from fused 5- to7-membered monocyclic carbocycle, fused 5- to 7-membered monocyclicheterocycle having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said fused Ring A is optionally substituted with one ormore R⁴⁰; R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R,—C(O)N(R)₂, or C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, areoptionally substituted with one or more R⁵⁰; each of R⁶ and R⁷ isindependently selected from H, halogen, —NO₂, —CN, —OR, —SR, —N(R)₂,—C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic; eachR is independently hydrogen or C₁₋₆ aliphatic, phenyl, 3- to 8-memberedsaturated or partially unsaturated carbocyclyl ring, 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, phenyl, 3- to7-membered saturated or partially unsaturated carbocyclyl ring, 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R⁵⁰; ortwo R groups on the same nitrogen are taken together with theirintervening atoms to form a ring selected from 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said ring is optionally substituted withone or more R⁵⁰; each R¹⁰ is independently selected from halogen,—OR^(10a), C₁₋₆aliphatic, 3- to 5-membered saturated or partiallyunsaturated carbocyclyl, 3- to 5-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, 3- to5-membered saturated or partially unsaturated carbocyclyl, 3- to5-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, areoptionally substituted with one or more R¹⁵; each R¹⁵ is independentlyselected from halogen and ˜OR^(15a); R^(10a) is C₁₋₆alkyl optionallysubstituted with halogen; R^(15a) is C₁₋₆alkyl; each R²⁰ isindependently selected from halogen, C₁₋₆ aliphatic, 3- to 5-memberedsaturated or partially unsaturated carbocyclyl, 3- to 5-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, wherein said C₁₋₆aliphatic, 3- to 5-membered saturated or partially unsaturatedcarbocyclyl, 3- to 5-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R¹⁵;each R⁴⁰ is independently selected from halogen, C₁₋₆ alkyl, 4- to6-membered monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, —C(O)H, —N(R^(40a))₂,—N(R^(40a))C(O)(R^(40b)), —N(R^(40a))C(O)₂(R^(40a)), —OR^(40a),—SR^(40a) and —C(O)₂R^(40a), wherein said C₁₋₆ alkyl group is optionallysubstituted with halogen or —OR^(40a); each R^(40a) is independentlyselected from H and C₁₋₆alkyl; or two R^(40a) groups on the samenitrogen are taken together with their intervening atoms to form a ringselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur; each R^(40b) isindependently selected from C₂₋₆ alkenyl and 5- or 6-memberedheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said 5- or 6-membered heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, is optionallysubstituted with one or more R⁴⁵; R⁴⁵ is C₁₋₆ alkyl; each R⁵⁰ isindependently selected from C₁₋₆ aliphatic, —OR^(50a), —N(R^(50a))₂,—C(O)N(R^(50a))₂, —C(O)₂R^(50a), oxo, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, wherein said C₁₋₆ alkyl, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, are optionally substituted with one or more R⁵⁵; R^(50a) isselected from H and C₁₋₆alkyl; each R⁵⁵ is independently selected from5- to 6-membered heterocyclyl having 1-2 heteroatoms selected fromnitrogen, oxygen, or sulfur, C₁₋₆ alkyl, —OR^(55a), —C(O)N(R^(55a))₂,halogen, —N(R^(55a))₂, —C(O)₂R^(55a), —S(O)₂R^(55b), and—S(O)₂(NR^(55a))₂; R^(55a) is selected from H and C₁₋₆alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with halogen; and R^(55b) isC₁₋₆ alkyl or a composition thereof.
 38. A method of treating a disorderresponsive to inhibition of Bruton's tyrosine kinase comprisingadministering to a subject an effective amount of a compound of FormulaI′:

or a pharmaceutically acceptable salt, wherein: one of A¹ and A² isC—R⁶, and the other of A¹ and A² is selected from C—R⁶ or N; A³ isselected from C—H or N, and is C—H when A¹ or A² is N; Q¹ is selectedfrom C—R⁷ and N; Q² is selected from C—R⁷ and N; Q³ is selected fromC—R⁷ and N; wherein at most one of Q¹, Q², and Q³ is N; R¹ is selectedfrom —N(R)₂, phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl areoptionally substituted with one or more R¹⁰; R² is H or C₁₋₆ aliphatic;or R¹ and R², together with their intervening atoms, form a ringselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, 7- to 10-membered bicyclic heterocyclyl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, or 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, wherein said ring is optionally substituted with oneor more R²⁰; R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR,—C(O)R, and C₁₋₆ aliphatic, wherein the C₁₋₆ aliphatic group isoptionally substituted with hydroxyl; each R⁴ is independently selectedfrom halogen, —NO₂, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R,—S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,—N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic, wherein said C₁₋₆ aliphaticis optionally substituted with one or more R⁴⁰; or R³ and R⁴ togetherwith their intervening atoms form fused Ring A selected from fused 5- to7-membered monocyclic carbocycle, fused 5- to 7-membered monocyclicheterocycle having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said fused Ring A is optionally substituted with one ormore R⁴⁰; R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R,—C(O)N(R)₂, or C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, areoptionally substituted with one or more R⁵⁰; each of R⁶ and R⁷ isindependently selected from H, halogen, —NO₂, —CN, —OR, —SR, —N(R)₂,—C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic; eachR is independently hydrogen or C₁₋₆ aliphatic, phenyl, 3- to 8-memberedsaturated or partially unsaturated carbocyclyl ring, 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, phenyl, 3- to7-membered saturated or partially unsaturated carbocyclyl ring, 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R⁵⁰; ortwo R groups on the same nitrogen are taken together with theirintervening atoms to form a ring selected from 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said ring is optionally substituted withone or more R⁵⁰; each R¹⁰ is independently selected from halogen,—OR^(10a), C₁₋₆aliphatic, 3- to 5-membered saturated or partiallyunsaturated carbocyclyl, 3- to 5-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, 3- to5-membered saturated or partially unsaturated carbocyclyl, 3- to5-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, areoptionally substituted with one or more R¹⁵; each R¹⁵ is independentlyselected from halogen and —OR^(15a); R^(10a) is C₁₋₆alkyl optionallysubstituted with halogen; R^(15a) is C₁₋₆alkyl; each R²⁰ isindependently selected from halogen, C₁₋₆ aliphatic, 3- to 5-memberedsaturated or partially unsaturated carbocyclyl, 3- to 5-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, wherein said C₁₋₆aliphatic, 3- to 5-membered saturated or partially unsaturatedcarbocyclyl, 3- to 5-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R¹⁵;each R⁴⁰ is independently selected from halogen, C₁₋₆ alkyl, 4- to6-membered monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, —C(O)H, —N(R^(40a))₂,—N(R^(40a))C(O)(R^(40b)), —N(R^(40a))C(O)₂(R^(40a)), —OR^(40a),—SR^(40a) and —C(O)₂R^(40a), wherein said C₁₋₆ alkyl group is optionallysubstituted with halogen or —OR^(40a); each R^(40a) is independentlyselected from H and C₁₋₆alkyl; or two R^(40a) groups on the samenitrogen are taken together with their intervening atoms to form a ringselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur; each R^(40b) isindependently selected from C₂₋₆ alkenyl and 5- or 6-memberedheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said 5- or 6-membered heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, is optionallysubstituted with one or more R⁴⁵; R⁴⁵ is C₁₋₆ alkyl; each R⁵⁰ isindependently selected from C₁₋₆ aliphatic, —OR^(50a), —N(R^(50a))₂,—C(O)N(R^(50a))₂, —C(O)₂R^(50a), oxo, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, wherein said C₁₋₆alkyl, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, are optionally substituted with one or more R⁵⁵; R^(50a) isselected from H and C₁₋₆alkyl; each R⁵⁵ is independently selected from5- to 6-membered heterocyclyl having 1-2 heteroatoms selected fromnitrogen, oxygen, or sulfur, C₁₋₆ alkyl, —OR^(55a), —C(O)N(R^(55a))₂,halogen, —N(R^(55a))₂, —C(O)₂R^(55a), —S(O)₂R^(55b), and—S(O)₂(NR^(55a))₂; R^(55a) is selected from H and C₁₋₆alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with halogen; and R^(55b) isC₁₋₆ alkyl or a composition thereof.
 39. A method of treating a disorderselected from the group consisting of autoimmune disorders, inflammatorydisorders, and cancers comprising administering to a subject aneffective amount of a compound of Formula I′:

or a pharmaceutically acceptable salt, wherein: one of A¹ and A² isC—R⁶, and the other of A¹ and A² is selected from C—R⁶ or N; A³ isselected from C—H or N, and is C—H when A¹ or A² is N; Q¹ is selectedfrom C—R⁷ and N; Q² is selected from C—R⁷ and N; Q³ is selected fromC—R⁷ and N; wherein at most one of Q¹, Q², and Q³ is N; R¹ is selectedfrom —N(R)₂, phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid phenyl, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-memberedsaturated or partially unsaturated bicyclic carbocyclyl, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl areoptionally substituted with one or more R¹⁰; R² is H or C₁₋₆ aliphatic;or R¹ and R², together with their intervening atoms, form a ringselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, 7- to 10-membered bicyclic heterocyclyl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, or 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, wherein said ring is optionally substituted with oneor more R²⁰; R³ is selected from H, halogen, —C(O)N(R)₂, —C(O)OR,—C(O)R, and C₁₋₆ aliphatic, wherein the C₁₋₆ aliphatic group isoptionally substituted with hydroxyl; each R⁴ is independently selectedfrom halogen, —NO₂, —CN, —OR, —SR, —N(R)₂, —C(O)R, —C(O)OR, —S(O)R,—S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,—N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic, wherein said C₁₋₆ aliphaticis optionally substituted with one or more R⁴⁰; or R³ and R⁴ togetherwith their intervening atoms form fused Ring A selected from fused 5- to7-membered monocyclic carbocycle, fused 5- to 7-membered monocyclicheterocycle having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said fused Ring A is optionally substituted with one ormore R⁴⁰; R⁵ is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O)₂R,—C(O)N(R)₂, or C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, whereinsaid C₁₋₆ aliphatic, phenyl, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to10-membered bicyclic heteroaryl having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl, areoptionally substituted with one or more R⁵⁰; each of R⁶ and R⁷ isindependently selected from H, halogen, —NO₂, —CN, —OR, —SR, —N(R)₂,—C(O)R, —C(O)OR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(O)OR, —N(R)SO₂R, —OC(O)N(R)₂, or C₁₋₆ aliphatic; eachR is independently hydrogen or C₁₋₆ aliphatic, phenyl, 3- to 8-memberedsaturated or partially unsaturated carbocyclyl ring, 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, phenyl, 3- to7-membered saturated or partially unsaturated carbocyclyl ring, 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R⁵⁰; ortwo R groups on the same nitrogen are taken together with theirintervening atoms to form a ring selected from 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur, wherein said ring is optionally substituted withone or more R⁵⁰; each R¹⁰ is independently selected from halogen,—OR^(10a), C₁₋₆aliphatic, 3- to 5-membered saturated or partiallyunsaturated carbocyclyl, 3- to 5-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein said C₁₋₆ aliphatic, 3- to5-membered saturated or partially unsaturated carbocyclyl, 3- to5-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, areoptionally substituted with one or more R¹⁵; each R¹⁵ is independentlyselected from halogen and —OR^(15a); R^(10a) is C₁₋₆alkyl optionallysubstituted with halogen; R^(15a) is C₁₋₆alkyl; each R²⁰ isindependently selected from halogen, C₁₋₆ aliphatic, 3- to 5-memberedsaturated or partially unsaturated carbocyclyl, 3- to 5-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, wherein said C₁₋₆aliphatic, 3- to 5-membered saturated or partially unsaturatedcarbocyclyl, 3- to 5-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur, are optionally substituted with one or more R¹⁵;each R⁴⁰ is independently selected from halogen, C₁₋₆ alkyl, 4- to6-membered monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, —C(O)H, —N(R^(40a))₂,—N(R^(40a))C(O)(R^(40b)), —N(R^(40a))C(O)₂(R^(40a)), —OR^(40a),—SR^(40a), and —C(O)₂R^(40a), wherein said C₁₋₆ alkyl group isoptionally substituted with halogen or —OR^(40a); each R^(40a) isindependently selected from H and C₁₋₆alkyl; or two R^(40a) groups onthe same nitrogen are taken together with their intervening atoms toform a ring selected from 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur; each R^(40b) isindependently selected from C₂₋₆ alkenyl and 5- or 6-memberedheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur, wherein said 5- or 6-membered heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, is optionallysubstituted with one or more R⁴⁵; R⁴⁵ is C₁₋₆ alkyl; each R⁵⁰ isindependently selected from C₁₋₆ aliphatic, —OR^(50a), —N(R^(50a))₂,—C(O)N(R^(50a))₂, —C(O)₂R^(50a), oxo, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, wherein said C₁₋₆ alkyl, 3- to 6-membered saturated orpartially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, and 3- to 10-memberedheterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, are optionally substituted with one or more R⁵⁵; R^(50a) isselected from H and C₁₋₆alkyl; each R⁵⁵ is independently selected from5- to 6-membered heterocyclyl having 1-2 heteroatoms selected fromnitrogen, oxygen, or sulfur, C₁₋₆ alkyl, —OR^(55a), —C(O)N(R^(55a))₂,halogen, —N(R^(55a))₂, —C(O)₂R^(55a), —S(O)₂R^(55b), and—S(O)₂(NR^(55a))₂; R^(55a) is selected from H and C₁₋₆alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with halogen; and R^(55b) isC₁₋₆ alkyl or a composition thereof.
 40. The method of claim 39, whereinthe disorder is rheumatoid arthritis.
 41. The method of claim 39,wherein the disorder is systemic lupus erythematosus.
 42. The method ofclaim 39, wherein the disorder is atopic dermatitis.
 43. The method ofclaim 39, wherein the disorder is leukemia or lymphoma.
 44. The methodof claim 39, wherein R¹ is selected from 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur,phenyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur, wherein R¹ is optionally substituted with one ormore R¹⁰.
 45. The method of claim 39, wherein R³ is hydrogen.
 46. Themethod of claim 39, R⁴ is halogen or C₁₋₆ aliphatic optionallysubstituted with one or more R⁴⁰, wherein R⁴⁰ is halogen.
 47. The methodof claim 39, wherein R³ and R⁴, together with their intervening atoms,form fused Ring A selected from fused 5- to 7-membered monocycliccarbocycle, and fused 5- to 7-membered heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, and sulfur.
 48. The methodof claim 39, wherein R⁵ is selected from hydrogen, —C(O)R, and 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, wherein the 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur is optionallysubstituted with one or more R⁵⁰.
 49. The method of claim 48, wherein R⁵is selected from pyrazolyl, imidazolyl, isoxazolyl, triazolyl,tetrazolyl, thiadiazolyl, and pyridyl, wherein R⁵ is optionallysubstituted with one or more R⁵⁰.
 50. The method of claim 49, wherein R⁵is


51. The method of claim 39, wherein each R⁶ is independently selectedfrom hydrogen, halogen, and C₁₋₆ aliphatic.
 52. The method of claim 39,wherein the compound is of formula VI-a or VI-c:

or a pharmaceutically acceptable salt thereof.